Publications by authors named "Yong Fen Qi"

131 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

Plasma Level of Elabela in Patients with Coronary Heart Disease and Its Correlation with the Disease Classification.

Int Heart J 2021 Jul 17;62(4):752-755. Epub 2021 Jul 17.

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

This study aimed to evaluate the concentration of plasma elabela (ELA) in patients with coronary heart disease (CHD) and its correlation with the disease classification.We enrolled 238 patients diagnosed by coronary angiography as CHD and 86 controls. The CHD group was divided into three subgroups: stable angina (SA), unstable angina (UAP), and acute myocardial infarction (AMI). The plasma levels of ELA were measured in all participants and compared among different groups. The relationship between ELA and CHD classification was analyzed.ELA levels were markedly higher by 10.71% in patients with CHD than in controls (P < 0.05). The concentration of ELA in UAP and AMI subgroups were higher than in controls and SA subgroup. The former difference was significant (P < 0.05), but the latter was not. In addition, the ELA concentration was not correlated with SYNTAX score, left ventricular ejection fraction, and other biochemical variables.The newfound hormone, ELA, significantly increased in patients with UAP and AMI. There is a tendency that ELA levels might be correlated with CHD classification, but not with lesion severity. ELA may play a role in acute coronary syndrome.
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http://dx.doi.org/10.1536/ihj.20-817DOI 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

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

Corrigendum to "Sustained activation of ADP/P2ry12 signaling induces SMC senescence contributing to thoracic aortic aneurysm/dissection" [Journal of molecular and cellular cardiology 99 (2016): 76-86.].

J Mol Cell Cardiol 2021 Aug 7;157:115-116. Epub 2020 Dec 7.

Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China. Electronic address:

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http://dx.doi.org/10.1016/j.yjmcc.2020.11.003DOI Listing
August 2021

STAT3 Promotes Schistosome-Induced Liver Injury by Inflammation, Oxidative Stress, Proliferation, and Apoptosis Signal Pathway.

Infect Immun 2021 02 16;89(3). Epub 2021 Feb 16.

Department of Pathogen Biology, School of Basic Medical Sciences, Peking University, Beijing, China

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms responsible for the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and mice were infected with cercariae of Liver injury, effector molecule levels, and RNA transcriptome resequencing of liver tissue were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 (signal transducer and activator of transcription 3) in -induced liver injury in mice. After 6 weeks postinfection, there was obvious liver fibrosis. A sustained pathological process (inflammation, oxidative stress, proliferation, and apoptosis) occurred in -induced liver fibrosis initiation. Meanwhile, we observed activation of the STAT3 pathway in hepatic injury during infection by RNA transcriptome resequencing. Liver deficiency of phospho-STAT3 alleviated infection-induced liver dysfunction, hepatic granuloma formation, and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress, and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation, and apoptosis are involved in -induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.
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http://dx.doi.org/10.1128/IAI.00309-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097265PMC
February 2021

STAT3: A key regulator in liver fibrosis.

Ann Hepatol 2021 Mar-Apr;21:100224. Epub 2020 Jul 21.

Department of Pathogen Biology, School of Basic Medical Sciences, Peking University, Beijing, China. Electronic address:

Janus protein tyrosine kinase (JAK) has the ability to activate signal transducer and activator of transcription (STAT). STAT3 is a valued member of the JAK/STAT signaling pathway. In recent years, several studies have documented that STAT3 is closely related to the occurrence and development of liver fibrosis caused by various factors. Activation of STAT3 can play anti- or pro-inflammatory roles in the pathogenesis of liver fibrosis. This article reviewed the recent studies on STAT3 in the development of various liver fibrosis to find a more effective method to relieve and cure liver diseases, such as hepatitis B virus (HBV), non-alcoholic fatty liver disease (NAFLD), schistosomiasis, and chemical liver injury.
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http://dx.doi.org/10.1016/j.aohep.2020.06.010DOI Listing
November 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

[New research advances in relationship of endoplasmic reticulum stress and cardiovascular diseases].

Sheng Li Xue Bao 2020 Apr;72(2):190-204

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

Endoplasmic reticulum (ER) is an important organelle for protein folding, post-transcriptional modification and transport, which plays an important role in maintaining cell homeostasis. A variety of internal and external environmental stimuli can cause the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum, and then result in ER stress. ER stress activates the unfolded protein response (UPR) and initiates a cluster of downstream signals to maintain ER homeostasis. However, severe and persistent ER stress activates UPR, which eventually leads to apoptosis and diseases. In recent years, a lot of researches suggest that ER stress plays an important role in the pathogenesis of various cardiovascular diseases (CVD), including ischemic heart disease, diabetic cardiomyopathy, heart failure, atherosclerosis and vascular calcification, high blood pressure and aortic aneurysm. ER stress might be one of the important targets for treatment of multiple CVD. Herein, the regulation mechanism of ER stress by activating UPR pathways in various common CVD and the new research advances in relationship of ER stress and CVD are briefly reviewed.
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April 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

Taurine Alleviates Schistosoma-Induced Liver Injury by Inhibiting the TXNIP/NLRP3 Inflammasome Signal Pathway and Pyroptosis.

Infect Immun 2019 12 18;87(12). Epub 2019 Nov 18.

Department of Pathogen Biology, School of Basic Medical Sciences, Peking University, Beijing, China

Schistosomiasis is a parasitic helminth disease that can cause severe inflammatory pathology, leading to organ damage, in humans. During a schistosomal infection, the eggs are trapped in the host liver, and products derived from eggs induce a polarized Th2 cell response, resulting in granuloma formation and eventually fibrosis. Previous studies indicated that the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in schistosomiasis-associated liver fibrosis and that taurine could ameliorate hepatic granulomas and fibrosis caused by infection. Nevertheless, the precise role and molecular mechanism of the NLRP3 inflammasome and the protective effects of taurine in infection have not been extensively studied. In this study, we investigated the role of the NLRP3 inflammasome and the hepatoprotective mechanism of taurine in schistosoma-induced liver injury in mice. NLRP3 deficiency ameliorated -infection-induced hepatosplenomegaly, liver dysfunction, and hepatic granulomas and fibrosis; it also reduced NLRP3-dependent liver pyroptosis. Furthermore, taurine suppressed hepatic thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in mice with infections, thereby inhibiting the activation of downstream inflammatory mediators such as interleukin-1β and subsequent pyroptosis. Our results suggest that the TXNIP/NLRP3 inflammasome pathway and mediating pyroptosis are involved in -induced liver injury and may be a potential therapeutic target for schistosomiasis treatment. In addition, taurine may be useful to alleviate or to prevent the occurrence of schistosomiasis-associated liver fibrosis.
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http://dx.doi.org/10.1128/IAI.00732-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867867PMC
December 2019

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

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

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

Protection Effect of Exogenous Fibroblast Growth Factor 21 on the Kidney Injury in Vascular Calcification Rats.

Chin Med J (Engl) 2018 Mar;131(5):532-538

Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029; Department of Cardiology, Beijing Aerospace General Hospital, Beijing 100076, China.

Background: Chronic kidney disease (CKD) is closely related to the cardiovascular events in vascular calcification (VC). However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 (FGF21) is an endocrine factor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases. Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats.

Methods: The male Sprague-Dawley rats were divided into three groups: (1) control group, (2) Vitamin D3 plus nicotine (VDN)-induced VC group, (3) FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases (ALPs) activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of β-Klotho and FGF receptor 1 (FGFR1) protein were measured by enzyme-linked immunosorbent assay (ELISA). The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining.

Results: The renal function impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% (34.750 ± 4.334 μmol/L vs. 27.630 ± 2.387 μmol/L) and 4.0% (7.038 ± 0.590 mmol/L vs. 6.763 ± 0.374 mmol/L; P < 0.01), respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% (P < 0.01) and 11.7% (P < 0.05) as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. ELISA assays showed that the expression of β-Klotho, a component of FGF21 receptor system, was increased in VDN-treated VC rats by 37.4% (6.588 ± 0.957 pg/mg vs. 9.054 ± 0.963 pg/mg; P < 0.01), indicating an FGF21-resistant state. Moreover, FGF21 treatment downregulated the level of β-Klotho in renal tissue by 16.7% (9.054 ± 0.963 pg/mg vs. 7.544 ± 1.362 pg/mg; P < 0.05). However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration (0.191 ± 0.0376 ng/mg vs. 0.189 ± 0.032 ng/mg vs. 0.181 ± 0.034 ng/mg; P > 0.05).

Conclusions: In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting off the vicious circle between VC and kidney injury.
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http://dx.doi.org/10.4103/0366-6999.226065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850668PMC
March 2018

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

Inhibition of Endoplasmic Reticulum Stress Apoptosis by Estrogen Protects Human Umbilical Vein Endothelial Cells Through the PI3 Kinase-Akt Signaling Pathway.

J Cell Biochem 2017 12 1;118(12):4568-4574. Epub 2017 Jun 1.

Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100000, China.

We aimed to investigate whether the cardioprotective effect of estrogen is mediated by inhibiting the apoptosis induced by endoplasmic reticulum stress (ERS) and to explore the underlying signaling pathway responsible for this effect. The effect of estrogen on ERS apoptosis, the mechanism responsible for that effect, and the ERS signaling pathways were examined in human umbilical vein endothelial cells (HUVECs) and measured using Western blot, Hoechst stains and caspase-3 activity assay. In vitro, 10 mol/l estrogen directly inhibited the up-regulation of the ERS marker glucose-regulated protein 78 (GRP78) and ERS apoptosis marker C/EBP homologous protein (CHOP). ERS was induced using the ERS inducer tunicamycin (TM, 10 µmol/l) or dithiothreitol (DTT, 2 mmol/l) in HUVECs. Estrogen can also decrease the apoptosis cells mediated by ERS, based on the results of Hoechst stains. Protein expression in the three main ERS signaling pathways was upregulated in TM- or DTT-induced HUVEC ERS. Increases in p-PERK/PERK were the most obvious, and estrogen significantly inhibited the upregulation of p-PERK/PERK, p-IRE1/IRE1, and ATF6. These inhibitory effects were abolished by specific estrogen receptor antagonists (ICI182, 780, and G15) and inhibitors of the E post-receptor signaling pathway, including phosphoinositide 3-kinase (PI3K) inhibitor LY294002, p38-mitogen activated protein kinase (p38-MAPK) inhibitor SB203580, c-Jun N-terminal kinase (JNK) inhibitor SP600125 and extracellular signal-regulated kinases1/2 (ERK1/2) inhibitor U0126; of these inhibitors, LY294002 was the most effective. Further experiments showed that when the PI3K pathway was blocked, the inhibitory effect of estrogen on ERS apoptosis was reduced. Estrogen can prevent HUVEC apoptosis by inhibiting the ERS apoptosis triggered by the PERK pathway, which may protect vascular endothelial cells and the cardiovascular system. The main mechanism responsible for ERS inhibition is the activation of the PI3K-Akt pathway for the activated estrogen receptor. J. Cell. Biochem. 118: 4568-4574, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.26120DOI Listing
December 2017

ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection.

Clin Sci (Lond) 2017 Jun 7;131(12):1287-1299. Epub 2017 Jun 7.

Beijing Anzhen Hospital, Capital Medical University; The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China

The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1β (IL-1β), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. , administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.
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http://dx.doi.org/10.1042/CS20170252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461939PMC
June 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

Sustained activation of ADP/P2ry12 signaling induces SMC senescence contributing to thoracic aortic aneurysm/dissection.

J Mol Cell Cardiol 2016 Oct 14;99:76-86. Epub 2016 Aug 14.

Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China. Electronic address:

Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-β-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans. High-performance liquid chromatography and luciferin-luciferase-based assay revealed that excessive mechanical stretch increased adenosine diphosphate (ADP) release from SMCs both in vivo and in vitro. Elevated ADP induced SMC senescence while genetic knockout of the ADP receptor, P2Y G protein-coupled receptor 12 (P2ry12), in mice protected against SMC senescence and inflammation. Both TAAD formation and rupture were significantly reduced in P2ry12 mice. SMCs from P2ry12 mice were resistant to senescence induced by excessive mechanical stretch or ADP treatment. Mechanistically, ADP treatment sustained Ras activation, whereas pharmacological inhibition of Ras protected against SMC senescence and reduced TAAD formation. Taken together, excessive mechanical stress may induce a sustained release of ADP and promote SMC senescence via P2ry12-dependent sustained Ras activation, thereby contributing to excessive inflammation and degeneration, which provides insights into TAAD formation and progression.
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http://dx.doi.org/10.1016/j.yjmcc.2016.08.008DOI Listing
October 2016

Taurine drinking ameliorates hepatic granuloma and fibrosis in mice infected with Schistosoma japonicum.

Int J Parasitol Drugs Drug Resist 2016 Apr 14;6(1):35-43. Epub 2016 Jan 14.

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

In schistosomiasis, egg-induced hepatic granuloma formation is a cytokine-mediated, predominantly CD4(+) Th2 immune response that can give rise to hepatic fibrosis. Hepatic fibrosis is the main cause of increased morbidity and mortality in humans with schistosome infection. Taurine has various physiological functions and hepatoprotective properties as well as anti-inflammatory and immunomodulatory activity. However, little is known about the role of taurine in schistosome egg-induced granuloma formation and fibrosis. We aimed to evaluate the therapeutic potential of taurine as preventative treatment for Schistosoma japonicum infection. Mice infected with S. japonicum cercariae were supplied with taurine drinking water (1% w/v) for 4 weeks starting at 4 weeks post-infection. Taurine supplementation significantly improved the liver pathologic findings, reduced the serum levels of aminotransferases and area of hepatic granuloma, and prevented fibrosis progression. In addition, taurine decreased the expression of the granulomatous and fibrogenic mediators transforming growth factor β1, tumor necrosis factor α, monocyte chemotactic protein 1α and macrophage inflammatory protein 1α as well as the endoplasmic reticulum stress marker glucose-regulated protein 78. Thus, taurine can significantly attenuate S. japonicum egg-induced hepatic granuloma and fibrosis, which may depend in part on the downregulation of some relevant cytokine/chemokines and reducing the endoplasmic reticulum stress response.
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http://dx.doi.org/10.1016/j.ijpddr.2016.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805782PMC
April 2016

Left Ventricular Noncompaction Combined With Epinephrine-Secreted Pheochromocytoma Inducing Heart Failure.

Int Heart J 2016 11;57(2):254-7. Epub 2016 Mar 11.

Department of Cardiology, Fu Xing Hospital, Capital Medical University.

Pheochromocytomas and left ventricular noncompaction (LVNC) are both rare diseases. In this patient, the long duration of the catecholamine-secreted pheochromocytoma caused myocardial ischemia, pressure overload, and hypertrophy, resulting in the onset of heart failure (HF). The LVNC might be associated with the acute attack of HF induced by the pheochromocytoma. This is the first case reporting LVNC in combination with HF secondary to pheochromocytoma.
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http://dx.doi.org/10.1536/ihj.15-311DOI Listing
August 2016

[Endogenous cardiovascular bioactive peptides and atrial fibrillation].

Sheng Li Ke Xue Jin Zhan 2015 Oct;46(5):375-8

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October 2015

Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of α-Klotho.

Kidney Int 2016 Mar 28;89(3):586-600. Epub 2016 Jan 28.

The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. Electronic address:

Deficiency in α-Klotho is involved in the pathogenesis of vascular calcification. Since intermedin (IMD)1-53 (a calcitonin/calcitonin gene-related peptide) protects against vascular calcification, we studied whether IMD1-53 inhibits vascular calcification by upregulating α-Klotho. A rat model of chronic kidney disease (CKD) with vascular calcification induced by the 5/6 nephrectomy plus vitamin D3 was used for study. The aortas of rats with CKD showed reduced IMD content but an increase of its receptor, calcitonin receptor-like receptor, and its receptor modifier, receptor activity-modifying protein 3. IMD1-53 treatment reduced vascular calcification. The expression of α-Klotho was greatly decreased in the aortas of rats with CKD but increased in the aortas of IMD1-53-treated rats with CKD. In vitro, IMD1-53 increased α-Klotho protein level in calcified vascular smooth muscle cells. α-Klotho knockdown blocked the inhibitory effect of IMD1-53 on vascular smooth muscle cell calcification and their transformation into osteoblast-like cells. The effect of IMD1-53 to upregulate α-Klotho and inhibit vascular smooth muscle cell calcification was abolished by knockdown of its receptor or its modifier protein, or treatment with the protein kinase A inhibitor H89. Thus, IMD1-53 may attenuate vascular calcification by upregulating α-Klotho via the calcitonin receptor/modifying protein complex and protein kinase A signaling.
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http://dx.doi.org/10.1016/j.kint.2015.12.029DOI Listing
March 2016

Whole Transcriptome Analysis of Hypertension Induced Cardiac Injury Using Deep Sequencing.

Cell Physiol Biochem 2016 8;38(2):670-82. Epub 2016 Feb 8.

Beijing Anzhen Hospital, Capital Medical University; The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education; Beijing Collaborative Innovation Center for Cardiovascular Disorders; Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing, China.

Background/aims: Hypertension plays a critical role in the cardiac inflammation and injury. However, the mechanism of how hypertension causes the cardiac injury at a molecular level remains to be elucidated.

Methods: RNA-Seq has been demonstrated to be an effective approach for transcriptome analysis, which is essential to reveal the molecular constituents of cells and tissues. In this study, we investigated the global molecular events associated with the mechanism of hypertension induced cardiac injury using RNA-Seq analysis.

Results: Our results showed that totally 1,801 genes with different expression variations were identified after Ang II infusion at 1, 3 and 7 days. Go analysis showed that the top 5 high enrichment Go terms were response to stress, response to wounding, cellular component organization, cell activation and defense response. KEGG pathway analysis revealed the top 5 significantly overrepresented pathways were associated with ECM-receptor interaction, focal adhesion, protein digestion and absorption, phagosome and asthma. Moreover, protein-protein interaction network analysis indicated that ubiquitin C may play a key role in the processes of hypertension-induced cardiac injury.

Conclusion: Our study provides a comprehensive understanding of the transcriptome events in hypertension-induced cardiac pathology.
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http://dx.doi.org/10.1159/000438659DOI Listing
November 2016

[Research Progress of Klotho].

Sheng Li Ke Xue Jin Zhan 2015 Aug;46(4):245-9

Klotho, a newly identified anti-aging gene, can be regulated by many factors, such as calcitonin gene-related peptide, fibroblast growth factor 2 could up-regulate Klotho expression; whereas renin-angiotensin system, urinary toxins, inflammation and oxidative stress could reduce expression of Klotho. There are two forms of Klotho protein: membrane-bound Klotho and secreted Klotho. Existing studies showed that Klotho was involved in the development of many diseases, including vascular calcification, atherosclerosis, hypertension, kidney damage, hyperparathyroidism, diabetes and tumors. In this paper, the regulation of Klotho expression and its role in diseases are reviewed briefly.
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August 2015
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