Publications by authors named "Chao Shu Tang"

321 Publications

Intermedin Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis.

Inflammation 2022 Feb 17. Epub 2022 Feb 17.

Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.

Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac fibrosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cardiac fibrosis. In this study, we aimed to investigate whether IMD mitigated cardiac fibrosis by inhibiting NLRP3. Cardiac fibrosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immunofluorescence assay, RNA sequencing, echocardiography, and hemodynamics were used to detect the role and the mechanism of IMD in cardiac fibrosis. Ang II infusion resulted in rat cardiac fibrosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) were found in Ang II-treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the fibrotic rat myocardium. IMD treatment attenuated the cardiac fibrosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA significantly promoted the Ang II-induced cardiac fibroblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting fibroblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3, and anti-fibrotic response. In conclusion, IMD alleviated cardiac fibrosis by inhibiting NLRP3 inflammasome activation through suppressing IRE1α via the cAMP/PKA pathway.
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http://dx.doi.org/10.1007/s10753-022-01642-zDOI Listing
February 2022

Baseline left ventricular ejection fraction associated with symptom improvements in both children and adolescents with postural tachycardia syndrome under metoprolol therapy.

Chin Med J (Engl) 2021 08 12;134(16):1977-1982. Epub 2021 Aug 12.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Postural tachycardia syndrome (POTS) is a common childhood disease that seriously affects the patient's physical and mental health. This study aimed to investigate whether pre-treatment baseline left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) values were associated with symptom improvement after metoprolol therapy for children and adolescents with POTS.

Methods: This retrospective study evaluated 51 children and adolescents with POTS who received metoprolol therapy at the Peking University First Hospital between November 2010 and July 2019. All patients had completed a standing test or basic head-up tilt test and cardiac echocardiography before treatment. Treatment response was evaluated 3 months after starting metoprolol therapy. The pre-treatment baseline LVEF and LVFS values were evaluated for correlations with decreases in the symptom score after treatment (ΔSS). Multivariable analysis was performed using factors with a P value of <0.100 in the univariate analyses and the demographic characteristics.

Results: A comparison of responders and non-responders revealed no significant differences in demographic, hemodynamic characteristics, and urine specific gravity (all P > 0.050). However, responders had significantly higher baseline LVEF (71.09% ± 4.44% vs. 67.17% ± 4.88%, t = -2.789, P = 0.008) and LVFS values (40.00 [38.00, 42.00]% vs. 36.79% ± 4.11%, Z = -2.542, P = 0.010) than the non-responders. The baseline LVEF and LVFS were positively correlated with ΔSS (r = 0.378, P = 0.006; r = 0.363, P = 0.009), respectively. Logistic regression analysis revealed that LVEF was independently associated with the response to metoprolol therapy in children and adolescents with POTS (odds ratio: 1.201, 95% confidence interval: 1.039-1.387, P = 0.013).

Conclusions: Pre-treatment baseline LVEF was associated with symptom improvement after metoprolol treatment for children and adolescents with POTS.
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http://dx.doi.org/10.1097/CM9.0000000000001698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382470PMC
August 2021

Interaction among Hydrogen Sulfide and Other Gasotransmitters in Mammalian Physiology and Pathophysiology.

Adv Exp Med Biol 2021 ;1315:205-236

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Hydrogen sulfide (HS), nitric oxide (NO), carbon monoxide (CO), and sulfur dioxide (SO) were previously considered as toxic gases, but now they are found to be members of mammalian gasotransmitters family. Both HS and SO are endogenously produced in sulfur-containing amino acid metabolic pathway in vivo. The enzymes catalyzing the formation of HS are mainly CBS, CSE, and 3-MST, and the key enzymes for SO production are AAT1 and AAT2. Endogenous NO is produced from L-arginine under catalysis of three isoforms of NOS (eNOS, iNOS, and nNOS). HO-mediated heme catabolism is the main source of endogenous CO. These four gasotransmitters play important physiological and pathophysiological roles in mammalian cardiovascular, nervous, gastrointestinal, respiratory, and immune systems. The similarity among these four gasotransmitters can be seen from the same and/or shared signals. With many studies on the biological effects of gasotransmitters on multiple systems, the interaction among HS and other gasotransmitters has been gradually explored. HS not only interacts with NO to form nitroxyl (HNO), but also regulates the HO/CO and AAT/SO pathways. Here, we review the biosynthesis and metabolism of the gasotransmitters in mammals, as well as the known complicated interactions among HS and other gasotransmitters (NO, CO, and SO) and their effects on various aspects of cardiovascular physiology and pathophysiology, such as vascular tension, angiogenesis, heart contractility, and cardiac protection.
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http://dx.doi.org/10.1007/978-981-16-0991-6_9DOI Listing
July 2021

Intermedin attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages.

Cell Death Dis 2021 05 1;12(5):436. Epub 2021 May 1.

Department of Physiology and Neurobiology, Medical College of Soochow University, 215123, Suzhou, China.

Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE) mice. Six-week IMD infusion significantly reduced atherosclerotic lesion size. Of note, IMD lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD administration prevented ERS activation in aortic lesions of ApoE mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE mice. IMD decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.
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http://dx.doi.org/10.1038/s41419-021-03712-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088440PMC
May 2021

Body mass index is a promising predictor of response to oral rehydration saline in children with vasovagal syncope.

Chin Med J (Engl) 2020 Nov 2;134(4):463-468. Epub 2020 Nov 2.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Vasovagal syncope (VVS) greatly impairs quality of life. The therapeutic efficacy of oral rehydration saline (ORS) for unselected VVS patients is not satisfactory due to the diverse mechanisms of the disease. Body mass index (BMI) was demonstrated to reflect blood volume to a certain extent. Therefore, the present study explored the capability of BMI to predict the therapeutic response of children with VVS to ORS treatment.

Methods: Seventy-four children with VVS who visited the Syncope Unit of Pediatrics at Peking University First Hospital from November 2010 to June 2019 receiving ORS treatment were enrolled for this retrospective case-control study. A comparison of demographic, clinical, and hemodynamic characteristics was performed between responders and non-responders. The correlation between baseline BMI and response time was analyzed. To determine the value of baseline BMI in predicting the therapeutic efficacy of ORS in children with VVS, a receiver operating characteristic curve analysis was performed.

Results: Fifty-two children were identified as responders, and the remaining 22 children were identified as non-responders. The baseline BMI of the responders was much lower than that of the non-responders (16.4 [15.5, 17.8] kg/m2vs. 20.7 ±e6 kg/m2, P < 0.001), and baseline BMI was positively correlated with response time in the head-up tilt test after adjusting for sex (r = 0.256, 95% confidence interval [CI]: 0.067-0.439, P = 0.029). The area under the receiver operating characteristic curve of baseline BMI was 0.818 (95% CI: 0.704-0.932, P < 0.001), and an optimal cut-off value of 18.9 kg/m2 yielded a sensitivity of 83% and a specificity of 73% to predict the efficacy of ORS in VVS.

Conclusion: Prior to treatment, baseline BMI is a promising predictor of response to ORS in children with VVS.
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http://dx.doi.org/10.1097/CM9.0000000000001168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909309PMC
November 2020

Inhibition of Notch1-mediated inflammation by intermedin protects against abdominal aortic aneurysm via PI3K/Akt signaling pathway.

Aging (Albany NY) 2021 02 1;13(4):5164-5184. Epub 2021 Feb 1.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.

The Notch1-mediated inflammatory response participates in the development of abdominal aortic aneurysm (AAA). The vascular endogenous bioactive peptide intermedin (IMD) plays an important role in maintaining vascular homeostasis. However, whether IMD inhibits AAA by inhibiting Notch1-mediated inflammation is unclear. In this study, we found Notch intracellular domain (NICD) and hes1 expression were higher in AAA patients' aortas than in healthy controls. In angiotensin II (AngII)-induced AAA mouse model, IMD treatment significantly reduced AAA incidence and maximal aortic diameter. IMD inhibited AngII-enlarged aortas and -degraded elastic lamina, reduced NICD, hes1 and inflammatory factors expression, decreased infiltration of CD68 positive macrophages and the NOD-like receptor family pyrin domain containing 3 protein level. IMD inhibited lipopolysaccharide-induced macrophage migration and regulated macrophage polarization. Moreover, IMD overexpression significantly reduced CaCl-induced AAA incidence and down-regulated NICD and hes1 expression. However, IMD deficiency showed opposite results. Mechanically, IMD treatment significantly decreased cleavage enzyme-a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) level. Pre-incubation with IMD (IMD receptors blocking peptide) and the phosphatidylinositol 3-kinase/protein kinase b (PI3K/Akt) inhibitor LY294002 reversed ADAM10 level. In conclusion, exogenous and endogenous IMD could inhibit the development of AAA by inhibiting Notch1 signaling-mediated inflammation via reducing ADAM10 through IMD receptor and PI3K/Akt pathway.
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http://dx.doi.org/10.18632/aging.202436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950288PMC
February 2021

Intermedin alleviates pathological cardiac remodeling by upregulating klotho.

Pharmacol Res 2020 09 2;159:104926. Epub 2020 Jun 2.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100083, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100083, China; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100083, China. Electronic address:

Cardiac remodeling is accompanied by cardiac hypertrophy, fibrosis, dysfunction, and eventually leading to heart failure. Intermedin (IMD), as a paracrine/autocrine peptide, has a protective effect in cardiovascular diseases. In this study, we elucidated the role and the underlying mechanism of IMD in pathological remodeling. Pathological remodeling mouse models were induced by abdominal aorta constriction for 4 weeks or angiotensin II (Ang II) infusion for 2 weeks in wildtype, IMD-overexpression, IMD-knockout and klotho-knockdown mice. Western blot, real-time PCR, histological staining, echocardiography and hemodynamics were used to detect the role of IMD in cardiac remodeling. Cardiac hypertrophy, fibrosis and dysfunction were significantly aggravated in IMD-knockout mice versus wildtype mice, and the expression of klotho was downregulated. Conversely, cardiac remodeling was alleviated in IMD-overexpression mice, and the expression of klotho was upregulated. Hypertension induced by Ang II infusion rather than abdominal aorta constriction was mitigated by IMD. However, the cardioprotective effect of IMD was blocked in klotho-knockdown mice. Similar results were found in cultured neonatal rat cardiomyocytes, which was pretreated with IMD before Ang II stimulation. Mechanistically, IMD inhibited the phosphorylation of Ca/calmodulin-dependent protein kinase II (CaMKII) and the activity of calcineurin to protect against cardiac hypertrophy through upregulating klotho in vivo and in vitro. Furthermore, peroxisome proliferator-activated receptor γ (PPARγ) might mediate IMD upregulating klotho. In conclusion, pathological remodeling may be alleviated by endogenous IMD, which inhibits the expression of calcineurin and p-CaMKII by upregulating klotho via the PPARγ pathway. It suggested that IMD might be a therapeutic target for heart disease.
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http://dx.doi.org/10.1016/j.phrs.2020.104926DOI Listing
September 2020

Intermedin attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1.

Aging (Albany NY) 2020 03 31;12(7):5651-5674. Epub 2020 Mar 31.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.

Vascular calcification is a common phenomenon in older adults. Intermedin (IMD) is a cardiovascular bioactive peptide inhibiting vascular calcification. In this study, we aimed to investigate whether IMD attenuates aging-associated vascular calcification. Vascular calcification was induced by vitamin D3 plus nicotine (VDN) in young and old rats. The calcification in aortas was more severe in old rats treated with VDN than young control rats, and IMD expression was lower. Exogenous administration of IMD significantly inhibited the calcium deposition in aortas and the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) in VDN-treated old rats. Moreover, levels of aging-related p16, p21 and β-galactosidase were all greatly decreased by IMD. These results were further confirmed in rat and human VSMCs . In addition, -deficient mouse VSMCs showed senescence features coinciding with osteogenic transition as compared with wild-type mouse VSMCs. Mechanistically, IMD significantly increased the expression of the anti-aging factor sirtuin 1 (sirt1); the inhibitory effects of IMD on calcification and senescence were blocked by knockdown. Furthermore, preincubation with inhibitors of PI3K, AMPK or PKA efficiently blunted the upregulatory effect of IMD on sirt1. Consequently, IMD could attenuate aging-associated vascular calcification by upregulating sirt1 via activating PI3K/Akt, AMPK and cAMP/PKA signaling.
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http://dx.doi.org/10.18632/aging.102934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185112PMC
March 2020

Intermedin Ameliorates Homocysteine-Promoted Atherosclerotic Calcification by Inhibiting Endoplasmic Reticulum Stress.

J Cardiovasc Pharmacol Ther 2020 05 7;25(3):251-264. Epub 2019 Nov 7.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, China.

Aim: Vascular calcification (VC) is thought to be an independent predictor of cardiovascular morbidity and mortality. Intermedin (IMD) is a cardiovascular protective peptide and can inhibit vascular medial calcification in rats. In this study, we investigated the effect of IMD on atherosclerotic calcification induced by a high-fat diet plus homocysteine (Hcy) and the potential mechanisms.

Methods: ApoE mice were fed a high-fat diet with Hcy in drinking water to induce atherosclerotic calcification.

Results: As compared to the high-fat diet alone, Hcy treatment significantly increased atherosclerotic lesion areas and the number of calcified nodules in aortic roots and was reduced by IMD infusion or 4-phenylbutyric acid (PBA) treatment. In vitro, as compared to calcifying medium alone, Hcy treatment further increased alkaline phosphatase activity, calcium content, and calcium nodule number in human aorta vascular smooth muscle cells (HA-VSMCs), all blocked by IMD or PBA pretreatment. Mechanistically, IMD or PBA significantly alleviated endoplasmic reticulum stress (ERS) activation compared with Hcy treatment. In parallel, IMD or PBA attenuated the messenger RNA levels of osteogenic markers and inflammatory cytokines in aortas and their protein levels in lesions of aortic roots. In vitro, Hcy treatment significantly increased the protein levels of osteoblast-like cell markers in primary rat VSMCs and inflammation markers in mouse peritoneal macrophages, all decreased with IMD or PBA pretreatment. Intermedin pretreatment also markedly reduced the protein levels of ERS markers in rat VSMCs and mouse peritoneal macrophages.

Conclusions: Intermedin protects against Hcy-promoted atherosclerotic calcification in ApoE mice by inhibiting ERS.
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http://dx.doi.org/10.1177/1074248419885633DOI Listing
May 2020

Endogenous intermedin protects against intimal hyperplasia by inhibiting endoplasmic reticulum stress.

Peptides 2019 11 10;121:170131. Epub 2019 Aug 10.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100083, China; Department of Pathogen Biology, School of Basic Medical Science, Peking University, Beijing 100083, China. Electronic address:

Extensive proliferation of vascular smooth muscle cell (VSMC) contributes to intimal hyperplasia following vascular injury, in which endoplasmic reticulum stress (ERS) plays a critical role. Intermedin (IMD) is a vascular paracrine/autocrine peptide exerting numerous beneficial effects in cardiovascular diseases. IMD overexpression could alleviate intimal hyperplasia. Here, we investigated whether endogenous IMD protects against intimal hyperplasia by inhibiting endoplasmic reticulum stress. The mouse left common carotid-artery ligation-injury model was established to induce intimal hyperplasia using IMDmice and C57BL/6 J wild-type (WT) mice. Platelet-derived growth factor-BB (PDGF-BB) was used to stimulate the proliferation of VSMC. IMD mice displayed exacerbated intimal hyperplasia induced by complete ligation of the left carotid artery at 14 d and 28 d compared to WT mice. However, IMD-deficiency had no effect on blood pressure, plasma triglyceride, and fasting blood glucose levels in mice. Furthermore, VSMCs derived from IMD mice showed increased cell proliferation and dramatically elevated levels of glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), ATF6 mRNA under PDGF-BB treatment compared to WT mice-derived VSMCs. In addition, exogenous administration of IMD significantly attenuated PDGF-BB-induced cell proliferation and GRP78, phosphorylase-inositol requiring enzyme 1α, ATF4, and ATF6 protein levels. Thus, endogenous IMD may counteract ERS to exert protective role in response to vascular injury and IMD is expected to be a therapeutic target for the prevention and treatment of restenosis.
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http://dx.doi.org/10.1016/j.peptides.2019.170131DOI Listing
November 2019

Irisin ameliorates angiotensin II-induced cardiomyocyte apoptosis through autophagy.

J Cell Physiol 2019 08 21;234(10):17578-17588. Epub 2019 Feb 21.

Deparment of Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II-treated cardiomyocytes, there is a larger cross-sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II-induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP-GFP-LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3-methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin-induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II-induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy.
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http://dx.doi.org/10.1002/jcp.28382DOI Listing
August 2019

Gut microbiota analysis and its significance in vasovagal syncope in children.

Chin Med J (Engl) 2019 Feb;132(4):411-419

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Vasovagal syncope (VVS) is common in children and greatly affect both physical and mental health. But the mechanisms have not been completely explained. This study was designed to analyze the gut microbiota in children with VVS and explore its clinical significance.

Methods: Fecal samples from 20 VVS children and 20 matched controls were collected, and the microbiota were analyzed by 16S rRNA gene sequencing. The diversity and microbiota compositions of the VVS cases and controls were compared with the independent sample t test or Mann-Whitney U test. The correlation between the predominant bacteria and clinical symptoms was analyzed using Pearson or Spearman correlation test.

Results: No significant differences in diversity were evident between VVS and controls (P > 0.05). At the family level, the relative abundance of Ruminococcaceae was significantly higher in VVS children than in controls (median [Q1, Q3]: 22.10% [16.89%, 27.36%] vs. 13.92% [10.31%, 20.18%], Z = -2.40, P < 0.05), and LEfSe analysis revealed Ruminococcaceae as a discriminative feature (linear discriminant analysis [LDA] score > 4, P < 0.05). The relative abundance of Ruminococcaceae in VVS patients was positively correlated with the frequency of syncope (r = 0.616, P < 0.01). In terms of its correlation with hemodynamics, we showed that relative abundance of Ruminococcaceae was negatively correlated with the systolic and diastolic pressure reduction at the positive response in head-up tilt test (HUTT; r = -0.489 and -0.448, all P < 0.05), but was positively correlated with the mean pressure drop and decline rate (r = 0.489 and 0.467, all P < 0.05) as well as diastolic pressure drop and decline rate at the HUTT positive response (r = 0.579 and 0.589, all P < 0.01) in VVS patients.

Conclusion: Ruminococcaceae was the predominant gut bacteria and was associated with the clinical symptoms and hemodynamics of VVS, suggesting that gut microbiota might be involved in the development of VVS.
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http://dx.doi.org/10.1097/CM9.0000000000000086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595724PMC
February 2019

Association of Circulating Neuregulin-4 with Presence and Severity of Coronary Artery Disease.

Int Heart J 2019 Jan 5;60(1):45-49. Epub 2018 Nov 5.

Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center.

Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD.We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD.Nrg4 levels were negatively associated with the SYNTAX score (r = -0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions.Nrg4 levels were found to be inversely associated with the presence and severity of CAD.
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http://dx.doi.org/10.1536/ihj.18-130DOI Listing
January 2019

Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway.

J Mol Cell Cardiol 2018 08 24;121:242-255. Epub 2018 Jul 24.

Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address:

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.
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http://dx.doi.org/10.1016/j.yjmcc.2018.07.250DOI Listing
August 2018

Inhibitory Effects of Sulfur Dioxide on Rat Myocardial Fibroblast Proliferation and Migration.

Chin Med J (Engl) 2018 Jul;131(14):1715-1723

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Myocardial fibrosis is an important pathological change in many heart diseases, but its pathogenesis is very complex and has not yet been fully elucidated. The study was designed to examine whether endogenous sulfur dioxide (SO) is a novel myocardial fibroblast proliferation and migration inhibitor.

Methods: Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase (AAT1 and AAT2) knockdown lentivirus or empty lentivirus. SO content in the supernatant was determined with high-performance liquid chromatography, and the expressions of AAT1, AAT2, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated protein kinase (p-ERK), and total ERK (T-ERK) in the cells were detected. Cell migration was detected by wound healing test. Independent sample t-test (for two groups) and one-way analysis of variance (three or more groups) were used to analyze the results.

Results: Both AAT1 and AAT2 knockdown significantly reduced SOlevels (F = 31.46, P < 0.01) and AAT1/2 protein expression (AAT1, t = 12.67, P < 0.01; AAT2, t = 9.61, P < 0.01), but increased PCNA expression and Cell Counting Kit-8 (CCK-8) activity as well as the migration in rat primary myocardial fibroblasts (P < 0.01). Supplementation of SOrather than pyruvate significantly inhibited the increase in proliferation and migration caused by AAT knockdown (P < 0.01). Mechanistically, the ratio of p-ERK to T-ERK was significantly increased in the AAT1/2 knockdown groups compared with that in the empty lentivirus group (AAT1, t = -7.36, P < 0.01; AAT2, t = -10.97, P < 0.01). Whereas PD98059, an inhibitor of ERK activation, successfully blocked AAT knockdown-induced PCNA upregulation (F = 74.01, P > 0.05), CCK-8 activation (F = 50.14, P > 0.05), and migration augmentation in myocardial fibroblasts (24 h, F = 37.08, P > 0.05; 48 h, F = 58.60, P > 0.05).

Conclusion: Endogenous SOmight be a novel myocardial fibroblast proliferation and migration inhibitor via inhibiting the ERK signaling pathway.
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http://dx.doi.org/10.4103/0366-6999.235875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048932PMC
July 2018

Inhibition of endoplasmic reticulum stress by intermedin1-53 attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE KO Mice.

Endocrine 2018 10 26;62(1):90-106. Epub 2018 Jun 26.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, 100083, Beijing, China.

Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1-53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII. Increased ERS levels were accompanied by severe VSMC apoptosis in human AAA aorta. In vivo administration of IMD1-53 greatly reduced AngII-induced AAA and abrogated the activation of ERS. To determine whether IMD inhibited AAA by ameliorating ERS, we used 2 non-selective ERS inhibitors phenyl butyrate (4-PBA) and taurine (TAU). Similar to IMD, PBA, and TAU significantly reduced the incidence of AAA and AAA-related pathological disorders. In vitro, AngII infusion up-regulated CHOP, caspase12 expression and led to VSMC apoptosis. IMD siRNA aggravated the CHOP, caspase12-mediated VSMC apoptosis, which was abolished by ATF4 silencing. IMD infusion promoted the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in aortas in ApoE KO mice, and the AMPK inhibitor compound C abolished the protective effect of IMD on VSMC ERS and apoptosis induced by AngII. In conclusion, IMD may protect against AAA formation by inhibiting ERS via activating AMPK phosphorylation.
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http://dx.doi.org/10.1007/s12020-018-1657-6DOI Listing
October 2018

Hydrogen Sulfide Regulating Myocardial Structure and Function by Targeting Cardiomyocyte Autophagy.

Chin Med J (Engl) 2018 Apr;131(7):839-844

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Objective: Hydrogen sulfide (HS), a gaseous signal molecule, plays a crucial role in many pathophysiologic processes in the cardiovascular system. Autophagy has been shown to participate in the occurrence of many cardiac diseases. Increasing evidences indicated that HS regulates myocardial structure and function in association with the altered autophagy and plays a "switcher" role in the autophagy of myocardial diseases. The aim of this review was to summarize these insights and provide the experimental evidence that HS targets cardiomyocyte autophagy to regulate cardiovascular function.

Data Sources: This review was based on data in articles published in the PubMed databases up to October 30, 2017, with the following keywords: "hydrogen sulfide," "autophagy," and "cardiovascular diseases."

Study Selection: Original articles and critical reviews on HS and autophagy were selected for this review.

Results: When autophagy plays an adaptive role in the pathogenesis of diseases, HS restores autophagy; otherwise, when autophagy plays a detrimental role, HS downregulates autophagy to exert a cardioprotective function. For example, HS has beneficial effects by regulating autophagy in myocardial ischemia/reperfusion and plays a protective role by inhibiting autophagy during the operation of cardioplegia and cardiopulmonary bypass. HS postpones cardiac aging associated with the upregulation of autophagy but improves the left ventricular function of smoking rats by lowering autophagy.

Conclusions: HS exerts cardiovascular protection by regulating autophagy. Cardiovascular autophagy would likely become a potential target of HS therapy for cardiovascular diseases.
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http://dx.doi.org/10.4103/0366-6999.228249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887743PMC
April 2018

Increased Endogenous Sulfur Dioxide Involved in the Pathogenesis of Postural Tachycardia Syndrome in Children: A Case-Control Study.

Chin Med J (Engl) 2018 Feb;131(4):435-439

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: The pathogenesis of postural tachycardia syndrome (POTS) remains unclear. This study aimed to explore the changes and significance of sulfur dioxide (SO) in patients with POTS.

Methods: The study included 31 children with POTS and 27 healthy children from Peking University First Hospital between December 2013 and October 2015. A detailed medical history, physical examination results, and demographic characteristics were collected. Hemodynamics was recorded and the plasma SOwas determined.

Results: The plasma SOwas significantly higher in POTS children compared to healthy children (64.0 ± 20.8 μmol/L vs. 27.2 ± 9.6 μmol/L, respectively, P < 0.05). The symptom scores in POTS were positively correlated with plasma SOlevels (r = 0.398, P < 0.05). In all the study participants, the maximum heart rate (HR) was positively correlated with plasma levels of SO(r = 0.679, P < 0.01). The change in systolic blood pressure from the supine to upright (ΔSBP) in POTS group was smaller than that in the control group (P < 0.05). The ΔSBP was negatively correlated with baseline plasma SOlevels in all participants (r = -0.28, P < 0.05). In the control group, ΔSBP was positively correlated with the plasma levels of SO(r = 0.487, P < 0.01). The change in HR from the supine to upright in POTS was obvious compared to that of the control group. The area under curve was 0.967 (95% confidence interval: 0.928-1.000), and the cutoff value of plasma SO level >38.17 μmol/L yielded a sensitivity of 90.3% and a specificity of 92.6% for predicting the diagnosis of POTS.

Conclusions: Increased endogenous SOlevels might be involved in the pathogenesis of POTS.
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http://dx.doi.org/10.4103/0366-6999.225051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830828PMC
February 2018

Plasma Neuropeptide Y Levels in Vasovagal Syncope in Children.

Chin Med J (Engl) 2017 Dec;130(23):2778-2784

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Vasovagal syncope (VVS) is the most common cause of syncope in children. Neuropeptide Y (NPY) plays an important role in the regulation of blood pressure (BP), as well as myocardial contractility. This study aimed to explore the role of plasma NPY in VVS in children.

Methods: Fifty-six children who were diagnosed with VVS (VVS group) using head-up tilt test (HUT) and 31 healthy children who were selected as controls (control group) were enrolled. Plasma NPY concentrations were detected. The independent t-test was used to compare the data of the VVS group with those of the control group. The changes in plasma NPY levels in the VVS group during the HUT, as well as hemodynamic parameters, such as heart rate (HR), BP, total peripheral vascular resistance (TPVR), and cardiac output (CO), were evaluated using the paired t-test. Furthermore, the correlations between plasma NPY levels and hemodynamic parameters were analyzed using bivariate correlation analysis.

Results: The BP, HR, and plasma NPY (0.34 ± 0.12 pg/ml vs. 0.46 ± 0.13 pg/ml) levels in the supine position were statistically low in the VVS group compared to levels in the control group (all P < 0.05). Plasma NPY levels were positively correlated with the HR (Pearson, R = 0.395, P < 0.001) and diastolic BP (Pearson, R = 0.311, P = 0.003) when patients were in the supine position. When patients in the VVS group were in the supine position, elevated TPVR (4.6 ± 3.7 mmHg·min-1·L-1 vs. 2.5 ± 1.0 mmHg·min-1·L-1, respectively, P < 0.001; 1 mmHg = 0.133 kPa) and reduced CO (1.0 ± 0.7 L/min vs. 2.4 ± 1.3 L/min, respectively, P < 0.001) were observed in the positive-response period compared with baseline values. The plasma NPY levels were positively correlated with TPVR (Spearman, R = 0.294, P = 0.028) but negatively correlated with CO in the positive-response period during HUT (Spearman, R = -0.318, P = 0.017).

Conclusions: Plasma NPY may contribute to the pathogenesis of VVS by increasing the TPVR and decreasing the CO during orthostatic regulation.
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http://dx.doi.org/10.4103/0366-6999.219157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717855PMC
December 2017

Intermedin reduces neointima formation by regulating vascular smooth muscle cell phenotype via cAMP/PKA pathway.

Atherosclerosis 2017 Nov 9;266:212-222. Epub 2017 Oct 9.

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100191, China; Department of Microbiology and Parasitology, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address:

Background And Aims: Vascular smooth muscle cell (VSMC) dedifferentiation contributes to neointima formation, which results in various vascular disorders. Intermedin (IMD), a cardiovascular paracrine/autocrine polypeptide, is involved in maintaining circulatory homeostasis. However, whether IMD protects against neointima formation remains largely unknown. The purpose of this study is to investigate the role of IMD in neointima formation and the possible mechanism.

Methods: IMD (100ng/kg/h) or saline water was used on rat carotid-artery balloon-injury model. The mouse left common carotid-artery ligation-injury model was established using IMD-transgenic and C57BL/6J mice. Immunohistochemistry and immunofluorescence staining was used to detect the protein expression in rat carotid arteries. Radioimmunoassay was used to determine the serum IMD level. The hematoxylin andeosin staining was used for carotid arteries morphological testing. In vitro, for rat primary cultured VSMC phenotype transition, proliferation and migration assays, platelet-derived growth factor-BB (PDGF-BB) reagent and IMD peptide were added to the culture media at the final concentration of 20 ng/mL and 10mol/L respectively. Quantification of VSMC proliferation involved MTT and BrdU assay and migration was detected by wound-healing assay. Western blot and realtime PCR were used to detect the protein and mRNA levels of tissues or cells.

Results: With the rat carotid-artery balloon-injury model, IMD was significantly downregulated in injured arteries and plasma. Exogenous IMD greatly inhibited neointima formation and prevented VSMC from switching to a synthetic phenotype. With the left common carotid-artery ligation-injury model, IMD-transgenic mice showed less neointima formation than C57BL/6J mice. PDGF-BB reduced IMD mRNA expression in rat primary cultured VSMCs but increased that of its receptors, calcitonin receptor-like receptor or receptor activity-modifying proteins. Furthermore, PDGF-BB promoted VSMC proliferation and migration and transformed VSMCs to the synthetic phenotype, which was reversed with IMD treatment. Mechanistically, IMD maintained the contractile VSMC phenotype via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway.

Conclusions: IMD attenuated neointima formation both in the rat model of carotid-artery balloon injury and mouse model of common carotid-artery ligation injury. IMD protection may be mediated by maintaining a VSMC contractile phenotype via the cAMP/PKA pathway.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.10.011DOI Listing
November 2017

Positive association between musclin and insulin resistance in obesity: evidence of a human study and an animal experiment.

Nutr Metab (Lond) 2017 10;14:46. Epub 2017 Jul 10.

Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, 150001 China.

Background: Musclin is a novel skeletal muscle-derived secretory factor considered to be a potent regulator of the glucose metabolism and therefore may contribute to the pathogenesis of obesity and insulin resistance (IR).

Methods: To test this hypothesis, we examined the plasma musclin levels in overweight/obese subjects and lean controls. Rats on a high fat diet (HFD) were used as the annimal model of obesity. Radioimmunoassay and western blot were used to determine musclin levels in plasma and skeletal muscle.

Results: According to radioimmunoassays,the overweight/obese subjects exhibited elevated musclin plasma levels compared with the lean controls (89.49 ± 19.00 ng/L vs 80.39 ± 16.35 ng/L,  < 0.01). The musclin levels were positively correlated with triglyceride, fasting plasma glucose, and homeostasis model assessment of IR levels. These observations were confirmed with a high-fat diet(HFD) rat model. HFD rats also exhibited increased musclin immunoreactivity in plasma ( < 0.01) and in skeletal muscle ( < 0.05), as well as increased musclin mRNA levels in skeletal muscle ( < 0.01). Musclin incubation significantly inhibited muscles H-2-DG uptake in the normal diet(ND) group ( < 0.01). The protein expression of glucose transporter type 4 was significantly down regulated by 30% ( < 0.05) in the ND group after soleusmuscle was incubated with musclin compared with the control. Musclin incubation also increased the protein levels of glucose-regulated protein (GRP)78 and GRP94 by 146.8 and 54% (both  < 0.05), respectively, in ND rats.

Conclusions: Our data support the hypothesis that musclin has a strong relationship with obesity-associated IR by impairing the glucose metabolism and, at least in part, through causing endoplasmic reticulum stress.
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http://dx.doi.org/10.1186/s12986-017-0199-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504815PMC
July 2017

Expressions of irisin and urotensin II and their relationships with blood pressure in patients with preeclampsia.

Clin Exp Hypertens 2017 23;39(5):460-467. Epub 2017 May 23.

a Department of Nephrology , Peking University Third Hospital , Beijing , China.

The aims of this study are to observe irisin and urotensin II (UII) levels in serum and placenta in normal pregnant and preeclamptic women and investigate the relationship between expressions irisin and UII, and their association with blood pressure. A total of 67 pregnant subjects were recruited, including 31 healthy and 36 preeclamptic pregnant women. Serum irisin and UII concentrations were measured. Expressions of fibronectin type III domain-containing protein 5 (FNDC5) (irisin precursor) and UII in placenta specimens were performed. There was no significant difference of serum irisin levels between severe preeclamptic (SPE)) patients, mild preeclamptic (MPE) patients and normal controls, while serum UII was significantly higher in preeclamptic women than normal pregnancy. There was no relationship between serum UII and irisin levels. In patients with preeclampsia, serum irisin was negatively associated with systolic and diastolic blood pressure(r = -0.350, P = 0.004, r = -0.307, P = 0.011), while serum UII was positively associated with systolic blood pressure (r = 0.291, P = 0.031). Serum irisin, UII, urinary protein level, BMI and serum creatinine were the independent determinants of blood pressure in preeclampsia by multiple regression analysis. Protein expression of FNDC5 and UII was upregulated in placenta of patients with SPE and positively correlated with systolic blood pressure and urinary protein level. We firstly verify that serum irisin and placental irisin precursor expressions have differently correlated with blood pressure. Expressions of irisin and urotensin II have relationships with blood pressure in patients with preeclampsia.
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http://dx.doi.org/10.1080/10641963.2016.1273945DOI Listing
March 2018

[Cardiovascular Regulation by Sulfur-containing Gaseous Signaling Molecules and the Underlying Mechanisms:Updated Research Evidence].

Sheng Li Ke Xue Jin Zhan 2017 Feb;48(1):4-11

The sulfur-containing gases hydrogen sulfide (H2S)and sulfur dioxide (SO2 )were previously considered to be waste gases. Recent studies showed that they could be endogenously generated from metabolism of the sulfur-containing amino acids in mammals. Endogenous H2S and SO2 generation pathways also existed in the cardiovascular system.H2S and SO2 had important physiological effects in the cardio-vascular system including vasorelaxation and myocardial negative inotropic effect. The pathophysiological effects of H2S and SO2 in the cardiovascular system have been recognized, such as alleviating hypertension and pulmonary hypertension, inhibiting the development of atherosclerosis, and protecting against myocardial ischemia-reperfusion (I /R)injury and isoproterenol-induced myocardial injury. Adenosine triphosphate-sensitive potassium (KATP )channel, L-type calcium (L-Ca2 +) channel, cGMP, NF-κB signaling pathway and MAPK signaling pathway and so on participated in the biological effects of H2S and SO2 .The above findings suggested that H2S and SO2 were important endogenous gaseous signaling molecules in the cardiovascular system, which provided a new way to elucidate the pathogenesis and therapeutic targets of cardiovascular diseases.
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February 2017

Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury.

Peptides 2017 02 16;88:196-207. Epub 2016 Dec 16.

Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing 100191, China; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address:

Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro, NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro. Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.
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http://dx.doi.org/10.1016/j.peptides.2016.12.009DOI Listing
February 2017

Intermedin Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice.

J Atheroscler Thromb 2016 Nov 6;23(11):1294-1306. Epub 2016 Apr 6.

Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center.

Aim: Endoplasmic reticulum stress (ERS) and inflammation participate in cardiac fibrosis. Importantly, a novel paracrine/autocrine peptide intermedin (IMD) in the heart inhibits myocardial fibrosis in rats. However, the mechanisms are yet to be fully elucidated.

Methods: Myocardial fibrosis in apolipoprotein E-deficient (ApoE -/-) mice and neonatal rat cardiac fibroblasts (CFs) were induced using homocysteine (Hcy).

Results: IMD inhibited myocardial fibrosis in vivo and in vitro. Picrosirius red staining showed that IMD reduced myocardial interstitial collagen deposition in ApoE-/- mice treated with Hcy and decreased the expression of myocardial collagen I and III, which was further verified in rat CFs. IMD attenuated myocardial hypertrophy, as shown by cardiomyocyte cross-sectional area, ratio of heart weight to body weight, and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. IMD inhibited the upregulation of ERS hallmarkers such as glucose-regulated protein 78 (GRP78), GRP94, activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1α, spliced-X-box-binding protein-1, protein kinase receptor-like ER kinase, and eukaryotic translation initiation factor 2α in mouse myocardium and rat CFs treated with Hcy. In addition, IMD decreased the production of inflammatory factors such as tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6 (IL-6), and IL-1β in the mouse myocardium and rat CFs treated with Hcy. Concurrently, IMD ameliorated the expression of nuclear factor-κB, transforming growth factor-β1, and c-Jun N-terminal kinase in the mouse myocardium and rat CFs treated with Hcy.

Conclusions: IMD potentially protects against myocardial fibrosis induced by Hcy in ApoE-/- mice, possibly via attenuating myocardial ERS and inflammation.
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http://dx.doi.org/10.5551/jat.34082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113747PMC
November 2016

Intermedin1-53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress.

Arterioscler Thromb Vasc Biol 2016 11 15;36(11):2176-2190. Epub 2016 Sep 15.

From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).

Objective: Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress.

Approach And Results: In angiotensin II-induced ApoE mouse and CaCl-induced C57BL/6J mouse model of AAA, IMD significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl. Mechanistically, IMD attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD. In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD and protein kinase A inhibitor H89 inhibited the effect of IMD, reducing Nox4 protein levels.

Conclusions: IMD could have a protective effect on AAA by inhibiting oxidative stress.
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http://dx.doi.org/10.1161/ATVBAHA.116.307825DOI Listing
November 2016

Sulfur Dioxide Inhibits Extracellular Signal-regulated Kinase Signaling to Attenuate Vascular Smooth Muscle Cell Proliferation in Angiotensin II-induced Hypertensive Mice.

Chin Med J (Engl) 2016 09;129(18):2226-32

Department of Pediatrics, Peking University First Hospital, Beijing 100034; Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing 100091, China.

Background: Clarifying the mechanisms underlying vascular smooth muscle cell (VSMC) proliferation is important for the prevention and treatment of vascular remodeling and the reverse of hyperplastic lesions. Previous research has shown that the gaseous signaling molecule sulfur dioxide (SO2) inhibits VSMC proliferation, but the mechanism for the inhibition of the angiotensin II (AngII)-induced VSMC proliferation by SO2has not been fully elucidated. This study was designed to investigate if SO2inhibited VSMC proliferation in mice with hypertension induced by AngII.

Methods: Thirty-six male C57 mice were randomly divided into control, AngII, and AngII + SO2groups. Mice in AngII group and AngII + SO2group received a capsule-type AngII pump implanted under the skin of the back at a slow-release dose of 1000 ng·kg-1·min-1. In addition, mice in AngII + SO2received intraperitoneal injections of SO2donor. Arterial blood pressure of tail artery was determined. The thickness of the aorta was measured by elastic fiber staining, and proliferating cell nuclear antigen (PCNA) and phosphorylated-extracellular signal-regulated kinase (P-ERK) were detected in aortic tissues. The concentration of SO2 in serum and aortic tissue homogenate supernatant was measured using high-performance liquid chromatography with fluorescence determination. In the in vitro study, VSMC of A7R5 cell lines was divided into six groups: control, AngII, AngII + SO2, PD98059 (an inhibitor of ERK phosphorylation), AngII + PD98059, and AngII + SO2 + PD98059. Expression of PCNA, ERK, and P-ERK was determined by Western blotting.

Results: In animal experiment, compared with the control group, AngII markedly increased blood pressure (P < 0.01) and thickened the aortic wall in mice (P < 0.05) with an increase in the expression of PCNA (P < 0.05). SO2, however, reduced the systemic hypertension and the wall thickness induced by AngII (P < 0.05). It inhibited the increased expression of PCNA and P-ERK induced by AngII (P < 0.05). In cell experiment, PD98059, an ERK phosphorylation inhibitor, blocked the inhibitory effect of SO2on VSMC proliferation (P < 0.05).

Conclusions: ERK signaling is involved in the mechanisms by which SO2inhibits VSMC proliferation in AngII-induced hypertensive mice via ERK signaling.
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http://dx.doi.org/10.4103/0366-6999.189927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022345PMC
September 2016

Urotensin II Induces ER Stress and EMT and Increase Extracellular Matrix Production in Renal Tubular Epithelial Cell in Early Diabetic Mice.

Kidney Blood Press Res 2016 13;41(4):434-49. Epub 2016 Jul 13.

Department of Nephrology, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.

Background/aims: Urotensin II (UII) and its receptor are highly expressed in the kidney tissue of patients with diabetic nephropathy (DN). The aim of this study is to examine the roles of UII in the induction of endoplasmic reticulum stress (ER stress) and Epithelial-mesenchymal transition (EMT) in DN in vivo and in vitro.

Methods: Kidney tissues were collected from patients with DN. C57BL/6 mice and mice with UII receptor knock out were injected with two consecutive doses of streptozotocin to induce diabetes and were sacrificed at 3th week for in vivo study. HK-2 cells in vitro were cultured and treated with UII. Markers of ER stress and EMT, fibronectin and type IV collagen were detected by immunohistochemistry, real time PCR and western blot.

Results: We found that the expressions of protein of UII, GRP78, CHOP, ALPHA-SMA, fibronectin and type IV collagen were upregulated while E-cadherin protein was downregulated as shown by immunohistochemistry or western blot analysis in kidney of diabetic mice in comparison to normal control; moreover expressions of GRP78, CHOP, ALPHA-SMA, fibronectin and type IV collagen were inhibited while E-caherin expression was enhanced in kidney in diabetic mice with UII receptor knock out in comparison to C57BL/6 diabetic mice. In HK-2 cells, UII induced upregulation of GRP78, CHOP, ALPHA-SMA, fibroblast-specifc protein 1(FSP-1), fibronectin and type collagen and downregulation of E-cadherin. UII receptor antagonist can block UII-induced ER stress and EMT; moreover, 4-PBA can inhibit the mRNA expression of ALPHA-SMA and FSP1 induced by UII in HK-2 cells.

Conclusions: We are the first to verify UII induces ER stress and EMT and increase extracellular matrix production in renal tubular epithelial cell in early diabetic mice. Moreover, UII may induce renal tubular epithelial EMT via triggering ER stress pathway in vitro, which might be the new pathogenic pathway for the development of renal fibrosis in DN.
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http://dx.doi.org/10.1159/000443445DOI Listing
March 2017

Retraction statement: ‘Urotensin II inhibits autophagy in renal tubular epithelial cells and induces extracellular matrix production in early diabetic mice’ by Guan‐Jong Chen, Fei Wu, Xin‐Xin Pang, Ai‐Hua Zhang, Jun‐Bao Shi, Min Lu and Chao‐Shu Tang

J Diabetes Investig 2017 07 26;8(4):629. Epub 2016 Jul 26.

Department of Pathology and Physiology, Peking University Health Science Center, Beijing, China.

Aims/introduction: Urotensin II (UII) and autophagy have been considered as important components in the pathogenesis of diabetic nephropathy. The present study explores whether UII can regulate autophagy in the kidney, and its effect in diabetes.

Materials And Methods: Immunohistochemistry and western blot were carried out on the kidney tissues of diabetic UII receptor (UT) gene knockout mice, wild-type diabetic mice and normal control mice. For the in vitro experiment, HK-2 cells were treated with UII (10 mol/L) in the presence or absence of UT antagonist, SB-657510, (10 mol/L) or autophagy inducer, rapamycin (10 mol/L), for 12 h. Markers for autophagy (LC3-II, p62/SQSTM1) and extracellular matrix (fibronectin, collagen IV) were analyzed.

Results: In diabetic UT knockout mice, expression of LC3-II is increased and p62 was reduced in comparison with that of the normal diabetic mice. Fibronectin and collagen IV were downregulated in diabetic UT knockout mice when compared with that of the normal diabetic mice. For the in vitro cell experiment, UII was shown to inhibit expression LC3-II and increase expression of p62 in comparison with that of the normal control. Treatment with SB-657510 can block UII-induced downregulation of LC3-II and upregulation of p62 while inhibiting UII-induced upregulation of fibronectin and collagen IV. Adding autophagy inducer, rapamycin, also inhibited UII-induced upregulation of fibronectin and collagen IV.

Conclusions: The present study is the first to show that UII can downregulate autophagy in the kidney while accompanying the increased production of extracellular matrix in early diabetes. Our in vitro study also showed that upregulation of autophagy can decrease UII-induced production of extracellular matrix in HK-2 cells.
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http://dx.doi.org/10.1111/jdi.12557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497045PMC
July 2017
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