Publications by authors named "Chunyu Zeng"

194 Publications

LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.

Cell Rep 2021 Nov;37(8):110038

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China. Electronic address:

Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
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http://dx.doi.org/10.1016/j.celrep.2021.110038DOI Listing
November 2021

Extracellular vesicles: Potential impact on cardiovascular diseases.

Adv Clin Chem 2021 10;105:49-100. Epub 2021 Mar 10.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Institute of Cardiology and Chongqing Key Laboratory for Hypertension Research, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Heart Center of Fujian Province, Union Hospital, Fujian Medical University, Fuzhou, PR China. Electronic address:

Extracellular vesicles (EVs) have received considerable attention in biological and clinical research due to their ability to mediate cell-to-cell communication. Based on their size and secretory origin, EVs are categorized as exosomes, microvesicles, and apoptotic bodies. Increasing number of studies highlight the contribution of EVs in the regulation of a wide range of normal cellular physiological processes, including waste scavenging, cellular stress reduction, intercellular communication, immune regulation, and cellular homeostasis modulation. Altered circulating EV level, expression pattern, or content in plasma of patients with cardiovascular disease (CVD) may serve as diagnostic and prognostic biomarkers in diverse cardiovascular pathologies. Due to their inherent characteristics and physiological functions, EVs, in turn, have become potential candidates as therapeutic agents. In this review, we discuss the evolving understanding of the role of EVs in CVD, summarize the current knowledge of EV-mediated regulatory mechanisms, and highlight potential strategies for the diagnosis and therapy of CVD. We also attempt to look into the future that may advance our understanding of the role of EVs in the pathogenesis of CVD and provide novel insights into the field of translational medicine.
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http://dx.doi.org/10.1016/bs.acc.2021.02.002DOI Listing
March 2021

Paternal long-term PM2.5 exposure causes hypertension via increased renal AT1R expression and function in male offspring.

Clin Sci (Lond) 2021 Nov;135(22):2575-2588

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

Maternal exposure to fine particulate matter (PM2.5) causes hypertension in offspring. However, paternal contribution of PM2.5 exposure to hypertension in offspring remains unknown. In the present study, male Sprague-Dawley rats were treated with PM2.5 suspension (10 mg/ml) for 12 weeks and/or fed with tap water containing an antioxidant tempol (1 mM/L) for 16 weeks. The blood pressure, 24 h-urine volume and sodium excretion were determined in male offspring. The offspring were also administrated with losartan (20 mg/kg/d) for 4 weeks. The expressions of angiotensin II type 1 receptor (AT1R) and G-protein-coupled receptor kinase type 4 (GRK4) were determined by qRT-PCR and immunoblotting. We found that long-term PM2.5 exposure to paternal rats caused hypertension and impaired urine volume and sodium excretion in male offspring. Both the mRNA and protein expression of GRK4 and its downstream target AT1R were increased in offspring of PM2.5-exposed paternal rats, which was reflected in its function because treatment with losartan, an AT1R antagonist, decreased the blood pressure and increased urine volume and sodium excretion. In addition, the oxidative stress level was increased in PM2.5-treated paternal rats. Administration with tempol in paternal rats restored the increased blood pressure and decreased urine volume and sodium excretion in the offspring of PM2.5-exposed paternal rats. Treatment with tempol in paternal rats also reversed the increased expressions of AT1R and GRK4 in the kidney of their offspring. We suggest that paternal PM2.5 exposure causes hypertension in offspring. The mechanism may be involved that paternal PM2.5 exposure-associated oxidative stress induces the elevated renal GRK4 level, leading to the enhanced AT1R expression and its-mediated sodium retention, consequently causes hypertension in male offspring.
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http://dx.doi.org/10.1042/CS20210802DOI Listing
November 2021

Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury.

J Hepatol 2021 Nov 1. Epub 2021 Nov 1.

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, P. R. China. Electronic address:

Background & Aims: Drug-induced liver injury (DILI) is a leading cause of acute liver failure, and treatment of DILI remains a challenge. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream whose physiological role in protection against DILI has not been examined.

Methods: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of MG53 or RIPK3. Live cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection.

Results: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation.

Conclusions: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI.

Lay Summary: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to the medical society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver-cell protection.
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http://dx.doi.org/10.1016/j.jhep.2021.10.017DOI Listing
November 2021

The Protective Role of Yin-Yang 1 in Cardiac Injury and Remodeling After Myocardial Infarction.

J Am Heart Assoc 2021 Nov 29;10(21):e021895. Epub 2021 Oct 29.

Department of Cardiology Daping Hospital Third Military Medical University Chongqing P. R. China.

Background Exploring potential therapeutic target is of great significance for myocardial infarction (MI) and post-MI heart failure. Transcription factor Yin-Yang 1 (YY1) is an essential regulator of apoptosis and angiogenesis, but its role in MI is unclear. Methods and Results The expression of YY1 was assessed in the C57BL/6J mouse heart following MI. Overexpression or silencing of YY1 in the mouse heart was achieved by adeno-associated virus 9 injection. The survival, cardiac function, and scar size, as well as the apoptosis, angiogenesis, cardiac fibrosis, T helper 2 lymphocyte cytokine production, and macrophage polarization were assessed. The effects of YY1 on Akt phosphorylation and vascular endothelial growth factor production were also investigated. The expression of YY1 in heart was significantly stimulated by MI. The survival rate, cardiac function, scar size, and left ventricular volume of mice were improved by YY1 overexpression but worsened by YY1 silencing. YY1 alleviated cardiac apoptosis and fibrosis, promoted angiogenesis, T helper 2 cytokine production, and M2 macrophage polarization in the post-MI heart, it also enhanced the tube formation and migration ability of endothelial cells. Enhanced Akt phosphorylation, along with the increased vascular endothelial growth factor levels were observed in presence of YY1 overexpression. Conclusions YY1 ameliorates cardiac injury and remodeling after MI by repressing cardiomyocyte apoptosis and boosting angiogenesis, which might be ascribed to the enhancement of Akt phosphorylation and the subsequent vascular endothelial growth factor up-regulation. Increased T helper 2 cytokine production and M2 macrophage polarization may also be involved in YY1's cardioprotective effects. These findings supported YY1 as a potential target for therapeutic investigation of MI.
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http://dx.doi.org/10.1161/JAHA.121.021895DOI Listing
November 2021

Calorie Restriction Protects against Contrast-Induced Nephropathy via SIRT1/GPX4 Activation.

Oxid Med Cell Longev 2021 19;2021:2999296. Epub 2021 Oct 19.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

Calorie restriction (CR) extends lifespan and increases resistance to multiple forms of stress, including renal ischemia-reperfusion (I/R) injury. However, whether CR has protective effects on contrast-induced nephropathy (CIN) remains to be determined. In this study, we evaluated the therapeutic effects of CR on CIN and investigated the potential mechanisms. CIN was induced by the intravenous injection of iodinated contrast medium (CM) iopromide (1.8 g/kg) into Sprague Dawley rats with normal food intake or 40% reduced food intake, 4 weeks prior to iopromide administration. We found that CR was protective of CIN, assessed by renal structure and function. CM increased apoptosis, reactive oxygen species (ROS), and inflammation in the renal outer medulla, which were decreased by CR. The silent information regulator 1 (SIRT1) participated in the protective effect of CR on CIN, by upregulating glutathione peroxidase 4 (GPX4), a regulator of ferroptosis, because this protective effect was reversed by EX527, a specific SIRT1 antagonist. Our study showed that CR protected CIN via SIRT1/GPX4 activation. CR may be used to mitigate CIN.
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http://dx.doi.org/10.1155/2021/2999296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548166PMC
October 2021

The Emerging Role of Irisin in Cardiovascular Diseases.

J Am Heart Assoc 2021 10 8;10(20):e022453. Epub 2021 Oct 8.

Department of Clinical Nutrition The Third Affiliated Hospital of Chongqing Medical University Chongqing China.

Irisin, a novel hormone like polypeptide, is cleaved and secreted by an unknown protease from a membrane-spanning protein, FNDC5 (fibronectin type III domain-containing protein 5). The current knowledge on the biological functions of irisin includes browning white adipose tissue, regulating insulin use, and anti-inflammatory and antioxidative properties. Dysfunction of irisin has shown to be involved in cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and myocardial ischemia-reperfusion injury. Moreover, irisin gene variants are also associated with cardiovascular diseases. In this review, we discuss the current knowledge on irisin-mediated regulatory mechanisms and their roles in the pathogenesis of cardiovascular diseases.
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http://dx.doi.org/10.1161/JAHA.121.022453DOI Listing
October 2021

Downregulation of AMPK/PPARδ Signaling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes.

Cardiovasc Res 2021 Aug 20. Epub 2021 Aug 20.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

Aims: Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes.

Methods And Results: Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation (EDR) in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor).

Conclusions: These results suggest an abnormal fetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signaling cascade.

Translational Perspective: Increasing evidence indicates that fetal programming is an important factor that contributes to the development of cardiovascular disease including hypertension and atherosclerosis later in life. This study explains the roles of AMPK/PPARδ/ER stress signaling cascade and endothelial dysfunction in maternal diabetes-programed adult hypertension in the offspring and provides a potential target for the prevention and therapy of this disease.
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http://dx.doi.org/10.1093/cvr/cvab280DOI Listing
August 2021

Impact of COVID-19 Pandemic on Mechanical Reperfusion in ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Multicenter Retrospective Study From a Non-epicenter Region.

Front Cardiovasc Med 2021 22;8:698923. Epub 2021 Jul 22.

Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital, Army Medical University, Chongqing, China.

The COVID-19 pandemic placed heavy burdens on emergency care and posed severe challenges to ST-segment-elevation myocardial infarction (STEMI) treatment. This study aimed to investigate the impact of COVID-19 pandemic on mechanical reperfusion characteristics in STEMI undergoing primary percutaneous coronary intervention (PPCI) in a non-epicenter region. STEMI cases undergoing PPCI from January 23 to March 29 between 2019 and 2020 were retrospectively compared. PPCI parameters mainly included total ischemic time (TIT), the period from symptom onset to first medical contact (S-to-FMC), the period from FMC to wire (FMC-to-W) and the period from door to wire (D-to-W). Furthermore, the association of COVID-19 pandemic with delayed PPCI risk was further analyzed. A total of 14 PPCI centers were included, with 100 and 220 STEMI cases undergoing PPCI in 2020 and 2019, respectively. As compared to 2019, significant prolongations occurred in reperfusion procedures ( < 0.001) including TIT (420 vs. 264 min), S-to-FMC (5 vs. 3 h), FMC-to-W (113 vs. 95 min) and D-to-W (83 vs. 65 min). Consistently, delayed reperfusion surged including TIT ≥ 12 h (22.0 vs.3.6%), FMC-to-W ≥ 120 min (34.0 vs. 6.8%) and D-to-W ≥ 90 min (19.0 vs. 4.1%). During the pandemic, the patients with FMC-to-W ≥ 120 min had longer durations in FMC to ECG completed (6 vs. 5 min, = 0.007), FMC to DAPT (24 vs. 21 min, = 0.001), catheter arrival to wire (54 vs. 43 min, < 0.001) and D-to-W (91 vs. 78 min, < 0.001). The pandemic was significantly associated with high risk of delayed PPCI (OR = 7.040, 95% CI 3.610-13.729, < 0.001). Even in a non-epicenter region, the risk of delayed STEMI reperfusion significantly increased due to cumulative impact of multiple procedures prolongation.
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http://dx.doi.org/10.3389/fcvm.2021.698923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339207PMC
July 2021

Gastrin mediates cardioprotection through angiogenesis after myocardial infarction by activating the HIF-1α/VEGF signalling pathway.

Sci Rep 2021 08 4;11(1):15836. Epub 2021 Aug 4.

Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.

Acute myocardial infarction (MI) is one of the leading causes of death in humans. Our previous studies showed that gastrin alleviated acute myocardial ischaemia-reperfusion injury. We hypothesize that gastrin might protect against heart injury after MI by promoting angiogenesis. An MI model was simulated by ligating the anterior descending coronary artery in adult male C57BL/6J mice. Gastrin was administered twice daily by intraperitoneal injection for 2 weeks after MI. We found that gastrin reduced mortality, improved myocardial function with reduced infarct size and promoted angiogenesis. Gastrin increased HIF-1α and VEGF expression. Downregulation of HIF-1α expression by siRNA reduced the proliferation, migration and tube formation of human umbilical vein endothelial cells. These results indicate that gastrin restores cardiac function after MI by promoting angiogenesis via the HIF-1α/VEGF pathway.
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http://dx.doi.org/10.1038/s41598-021-95110-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339006PMC
August 2021

DRD4 (Dopamine D4 Receptor) Mitigate Abdominal Aortic Aneurysm via Decreasing P38 MAPK (mitogen-activated protein kinase)/NOX4 (NADPH Oxidase 4) Axis-Associated Oxidative Stress.

Hypertension 2021 Aug 28;78(2):294-307. Epub 2021 Jun 28.

The Hospital Affiliated to Medical School of Yangzhou University (Taizhou People's Hospital), China (Y.Y., D.W.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16738DOI Listing
August 2021

Increased AT receptor expression mediates vasoconstriction leading to hypertension in Snx1 mice.

Hypertens Res 2021 Aug 10;44(8):906-917. Epub 2021 May 10.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

Angiotensin II type 1 receptor (ATR) is a vital therapeutic target for hypertension. Sorting nexin 1 (SNX1) participates in the sorting and trafficking of the renal dopamine D receptor, while angiotensin and dopamine are counterregulatory factors in the regulation of blood pressure. The effect of SNX1 on ATR is not known. We hypothesized that SNX1, through arterial ATR sorting and trafficking, is involved in blood pressure regulation. CRISPR/Cas9 system-generated SNX1 mice showed dramatic elevations in blood pressure compared to their wild-type littermates. The angiotensin II-mediated contractile reactivity of the mesenteric arteries and ATR expression in the aortas were also increased. Moreover, immunofluorescence and immunoprecipitation analyses revealed that SNX1 and ATR were colocalized and interacted in the aortas of wild-type mice. In vitro studies revealed that ATR protein levels and downstream calcium signaling were upregulated in A10 cells treated with SNX1 siRNA. This may have resulted from decreased ATR protein degradation since the ATR mRNA levels showed no changes. ATR protein was less degraded when SNX1 was downregulated, as reflected by a cycloheximide chase assay. Furthermore, proteasomal rather than lysosomal inhibition increased ATR protein content, and this effect was accompanied by decayed binding of ubiquitin and ATR after SNX1 knockdown. Confocal microscopy revealed that ATR colocalized with PSMD6, a proteasomal marker, and the colocalization was reduced after SNX1 knockdown. These findings suggest that SNX1 sorts ATR for proteasomal degradation and that SNX1 impairment increases arterial ATR expression, leading to increased vasoconstriction and blood pressure.
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http://dx.doi.org/10.1038/s41440-021-00661-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590203PMC
August 2021

Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients.

Clin Exp Hypertens 2021 Oct 25;43(7):597-603. Epub 2021 Apr 25.

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, P.R. China.

: Genetic variants of coding genes related to blood pressure regulation participate in the pathogenesis of hypertension and determines the response to specific antihypertensive drugs. G protein-coupled receptor kinase 4 (GRK4) and its variants are of great importance in pathogenesis of hypertension. However, little is known about role of GRK4 variants in determine circadian rhythm of blood pressure and response to candesartan in hypertension. The aim of this study was to analyze the correlation of GRK4 variants and circadian rhythm of blood pressure, and to explore their effect on antihypertensive efficiency of candestartan. In this study, a total of 1239 cases were eligible, completed ambulatory blood pressure monitoring (ABPm) observation and exon sequencing of G protein-coupled receptor kinase 4 (GRK4). ABPm was obtained before and after 4-week treatment of candesartan. Diurnal variation of systolic blood pressure and antihypertensive effect of candesartan were then assessed. Compared to GRK4 wild type (GRK4-WT), patients with GRK4 variants were more likely to be non-dippers (), with GRK4 A142V (OR 5.888, 95% CI 4.332-8.003, < .001), A486V (OR 7.102, 95% CI 5.334-9.455, < .001) and GRK4 R65L (OR 3.273, 95% CI 2.271-4.718, < .001), respectively. Correlation analysis revealed that non-dippers rhythm of blood pressure were associated with GRK4 variants (r = .420, < .001), with GRK4 A142V (r = .416, < .001), A486V (r = .465, < .001) and GRK4 R65L (r = .266, < .001), respectively. When given 4-week candesartan, patients with GRK4 variants showed better antihypertensive effect as to drop in blood pressure (24 h mSBP, ) and morning peak (MP-SBP, ), as well as greater increase in trough to peak ratio (SBP-T/P, .) and smoothness index (SBP-SI, ) than those with GRK4 WT. This study indicates that hypertensive patients with GRK4 variants are more likely to be non-dippers. What's more, patients with GRK4 variants possess a significantly better antihypertensive response to candesartan than those with GRK4 WT.
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http://dx.doi.org/10.1080/10641963.2021.1919357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565180PMC
October 2021

Mitochondrial Damage-Induced Innate Immune Activation in Vascular Smooth Muscle Cells Promotes Chronic Kidney Disease-Associated Plaque Vulnerability.

Adv Sci (Weinh) 2021 Mar 6;8(5):2002738. Epub 2021 Jan 6.

Department of Nephrology the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing Kidney Center of PLA Xinqiao Hospital Army Medical University (Third Military Medical University) Chongqing 400037 China.

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E-deficient (ApoE) mouse with CKD (CKD/ApoE mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD-associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE mice are comprehensively investigated. Using multi-omics analysis and targeted and VSMC-specific gene knockout mice, VSMCs are identified as both type-I-interferon (IFN-I)-responsive and IFN-I-productive cells. Mechanistically, mitochondrial damage resulting from CKD-induced oxidative stress primes the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to trigger IFN-I response in VSMCs. Enhanced IFN-I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN-I response remarkably attenuates CKD-associated plaque vulnerability. These findings reveal that IFN-I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD-associated plaque vulnerability. Mitigating IFN-I response may hold promise for the treatment of CKD-associated cardiovascular diseases.
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http://dx.doi.org/10.1002/advs.202002738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927614PMC
March 2021

Coronary Anomalies in 11,267 Southwest Chinese Patients Determined by Angiography.

Biomed Res Int 2021 18;2021:6693784. Epub 2021 Feb 18.

Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Army Medical University, Chongqing 400042, China.

Background: The prevalence of coronary artery anomalies (CAAs) is rare and varies among different countries or areas. More importantly, the symptoms exhibited by some CAAs make the diagnosis of coronary artery disease (CAD) difficult and hamper the physician from making the right intervention for CAD patients.

Objective: To investigate the prevalence of CAAs in 11,267 patients from three hospitals in Southwest China.

Methods: 11,267 patients who have undergone coronary angiography from three Southwest China hospitals were investigated retrospectively. Dominance patterns, prevalence, and the location of each CAA were recorded and analyzed.

Results: The presence of a dominant right coronary artery (RCA) was found in 60.58% of patients. CAAs were found in 11.12% (1258) patients, and 87.66% anomalies were located in the left anterior descending (LAD) artery and its branches. Most of CAAs were found to be myocardial bridges (MBs, 1060 cases, 9.41%). Other CAAs included anomalous coronary origin (43 cases, 0.38%), coronary artery fistulas (CAFs, 36 cases, 0.32%), and coronary artery aneurysm or ectasia (119 cases, 1.06%). It also noted that most anomalies were found with RCA originating from the left coronary sinus (79.07%), most CAFs were located in the LAD and its branches (58.33%), and most coronary artery ectasias were located in the RCA (43.25%).

Conclusions: CAAs in patients from Southwest China were unique compared to other studies. Recognition of these CAAs is important for accurate diagnosis and treatment choice of patients with chest pain.
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http://dx.doi.org/10.1155/2021/6693784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910051PMC
May 2021

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

Circulation 2021 May 5;143(20):2007-2022. Epub 2021 Mar 5.

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).

Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.

Methods: We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.

Results: LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.

Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050812DOI Listing
May 2021

Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons.

Protein Cell 2021 07 6;12(7):545-556. Epub 2021 Feb 6.

Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.

Activation of the heart normally begins in the sinoatrial node (SAN). Electrical impulses spontaneously released by SAN pacemaker cells (SANPCs) trigger the contraction of the heart. However, the cellular nature of SANPCs remains controversial. Here, we report that SANPCs exhibit glutamatergic neuron-like properties. By comparing the single-cell transcriptome of SANPCs with that of cells from primary visual cortex in mouse, we found that SANPCs co-clustered with cortical neurons. Tissue and cellular imaging confirmed that SANPCs contained key elements of glutamatergic neurotransmitter system, expressing genes encoding glutamate synthesis pathway (Gls), ionotropic and metabotropic glutamate receptors (Grina, Gria3, Grm1 and Grm5), and glutamate transporters (Slc17a7). SANPCs highly expressed cell markers of glutamatergic neurons (Snap25 and Slc17a7), whereas Gad1, a marker of GABAergic neurons, was negative. Functional studies revealed that inhibition of glutamate receptors or transporters reduced spontaneous pacing frequency of isolated SAN tissues and spontaneous Ca transients frequency in single SANPC. Collectively, our work suggests that SANPCs share dominant biological properties with glutamatergic neurons, and the glutamatergic neurotransmitter system may act as an intrinsic regulation module of heart rhythm, which provides a potential intervention target for pacemaker cell-associated arrhythmias.
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http://dx.doi.org/10.1007/s13238-020-00820-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225718PMC
July 2021

Importance of extracellular vesicles in hypertension.

Exp Biol Med (Maywood) 2021 02 6;246(3):342-353. Epub 2020 Dec 6.

Cardiovascular Research Center of Chongqing College, Department of Cardiology of Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400714, P.R. China.

Hypertension affects approximately 1.13 billion adults worldwide and is the leading global risk factor for cardiovascular, cerebrovascular, and kidney diseases. There is emerging evidence that extracellular vesicles participate in the development and progression of hypertension. Extracellular vesicles are membrane-enclosed structures released from nearly all types of eukaryotic cells. During their formation, extracellular vesicles incorporate various parent cell components, including proteins, lipids, and nucleic acids that can be transferred to recipient cells. Extracellular vesicles mediate cell-to-cell communication in a variety of physiological and pathophysiological processes. Therefore, studying the role of circulating and urinary extracellular vesicles in hypertension has the potential to identify novel noninvasive biomarkers and therapeutic targets of different hypertension phenotypes. This review discusses the classification and biogenesis of three EV subcategories (exosomes, microvesicles, and apoptotic bodies) and provides a summary of recent discoveries in the potential impact of extracellular vesicles on hypertension with a specific focus on their role in the blood pressure regulation by organs-artery and kidney, as well as renin-angiotensin-system.
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http://dx.doi.org/10.1177/1535370220974600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876642PMC
February 2021

Gastrin, via activation of PPARα, protects the kidney against hypertensive injury.

Clin Sci (Lond) 2021 01;135(2):409-427

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.
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http://dx.doi.org/10.1042/CS20201340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594318PMC
January 2021

Endothelial Nox4 dysfunction aggravates atherosclerosis by inducing endoplasmic reticulum stress and soluble epoxide hydrolase.

Free Radic Biol Med 2021 02 5;164:44-57. Epub 2021 Jan 5.

Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China. Electronic address:

Background And Aims: Our previous findings have demonstrated the protective effect of endothelial Nox4-based NADPH oxidase on atherosclerosis. One of the possible mechanisms is the inhibition of soluble epoxide hydrolase (sEH), a proinflammatory and atherogenic factor. Our goal was to investigate whether in vivo inhibition of sEH by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) alleviates endothelial Nox4 dysfunction caused atherosclerosis and the regulatory mechanism of endothelial Nox4 on sEH.

Methods: & results: We used endothelial human Nox4 dominant-negative (EDN) transgenic mice in ApoE deficient background to mimic the dysfunction of endothelial Nox4 in atherosclerosis-prone conditions. In EDN aortic endothelium, sEH and the inflammatory marker vascular cell adhesion molecule 1 (VCAM1) were upregulated. TPPU reduced atherosclerotic lesions in EDN mice. In EDN endothelial cells (ECs), the endoplasmic reticulum (ER) stress markers (BIP, IRE1α, phosphorylation of PERK, ATF6) were upregulated, and they can be suppressed by ER stress inhibitor 4-phenyl butyric acid (4-PBA). In EDN ECs, 4-PBA downregulated the expression of sEH and VCAM1, suppressed inflammation, and its application in vivo reduced atherosclerotic lesions of EDN mice.

Conclusions: Endothelial Nox4 dysfunction upregulated sEH to enhance inflammation, probably by its induction of ER stress. Inhibition of ER stress or sEH is beneficial to alleviate atherosclerosis caused by endothelial Nox4 dysfunction.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.450DOI Listing
February 2021

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Nat Commun 2021 01 4;12(1):102. Epub 2021 Jan 4.

Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, 400038, China.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.
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http://dx.doi.org/10.1038/s41467-020-20315-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782823PMC
January 2021

Gastrin Attenuates Renal Ischemia/Reperfusion Injury by a PI3K/Akt/Bad-Mediated Anti-apoptosis Signaling.

Front Pharmacol 2020 6;11:540479. Epub 2020 Nov 6.

Department of Cardiology, Daping Hospital, Army Medical University, Chongqing, China.

Ischemic/reperfusion (I/R) injury is the primary cause of acute kidney injury (AKI). Gastrin, a gastrointestinal hormone, is involved in the regulation of kidney function of sodium excretion. However, whether gastrin has an effect on kidney I/R injury is unknown. Here we show that cholecystokinin B receptor (CCKBR), the gastrin receptor, was significantly up-regulated in I/R-injured mouse kidneys. While pre-administration of gastrin ameliorated I/R-induced renal pathological damage, as reflected by the levels of serum creatinine and blood urea nitrogen, hematoxylin and eosin staining and periodic acid-Schiff staining. The protective effect could be ascribed to the reduced apoptosis for gastrin reduced tubular cell apoptosis both and . studies also showed gastrin preserved the viability of hypoxia/reoxygenation (H/R)-treated human kidney 2 (HK-2) cells and reduced the lactate dehydrogenase release, which were blocked by CI-988, a specific CCKBR antagonist. Mechanistically, the PI3K/Akt/Bad pathway participates in the pathological process, because gastrin treatment increased phosphorylation of PI3K, Akt and Bad. While in the presence of wortmannin (1 μM), a PI3K inhibitor, the gastrin-induced phosphorylation of Akt after H/R treatment was blocked. Additionally, wortmannin and Akt inhibitor VIII blocked the protective effect of gastrin on viability of HK-2 cells subjected to H/R treatment. These studies reveals that gastrin attenuates kidney I/R injury via a PI3K/Akt/Bad-mediated anti-apoptosis signaling. Thus, gastrin can be considered as a promising drug candidate to prevent AKI.
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http://dx.doi.org/10.3389/fphar.2020.540479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7740972PMC
November 2020

The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction.

Eur Heart J 2021 04;42(14):1415-1430

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.

Aims: G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI.

Methods And Results: We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers.

Conclusion: GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.
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http://dx.doi.org/10.1093/eurheartj/ehaa878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026279PMC
April 2021

An Aurora Kinase B-Based Mouse System to Efficiently Identify and Analyze Proliferating Cardiomyocytes.

Front Cell Dev Biol 2020 7;8:570252. Epub 2020 Oct 7.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

To identify and analyze the live proliferating cardiomyocytes is crucial for deciphering the mechanisms controlling endogenous cardiac regeneration. Traditional methods confuse cell division with multinucleation in postnatal cardiomyocytes. Recent efforts have achieved significant progress on discerning cytokinesis from only nuclear division. However, those methods were either designed to label post-cytokinesis progeny or challenging to sort the live proliferating cardiomyocytes. In this study, we highlighted an Aurora kinase B reporter-based mouse system with a tdTomato fluorescence labeling. It could efficiently identify proliferating cardiomyocytes in neonates. The analysis of sorting tdTomato cardiomyocytes with different ploidy indicated that mononucleated cardiomyocytes might not possess significantly higher proliferating potential than other cardiomyocytes when most cardiomyocytes have become post-mitotic. Moreover, tdTomato cardiomyocytes were significantly increased and enriched at injury border zone after apex resection in neonates, while there were no increased tdTomato cardiomyocytes after myocardial infarction in adults.
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http://dx.doi.org/10.3389/fcell.2020.570252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575716PMC
October 2020

Progesterone, via yes-associated protein, promotes cardiomyocyte proliferation and cardiac repair.

Cell Prolif 2020 Nov 12;53(11):e12910. Epub 2020 Oct 12.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

Objectives: The mechanisms responsible for the postnatal loss of mammalian cardiac regenerative capacity are not fully elucidated. The aim of the present study is to investigate the role of progesterone in cardiac regeneration and explore underlying mechanism.

Materials And Methods: Effect of progesterone on cardiomyocyte proliferation was analysed by immunofluorescent staining. RNA sequencing was performed to screen key target genes of progesterone, and yes-associated protein (YAP) was knocked down to demonstrate its role in pro-proliferative effect of progesterone. Effect of progesterone on activity of YAP promoter was measured by luciferase assay and interaction between progesterone receptor and YAP promoter by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Adult mice were subjected to myocardial infarction, and then, effects of progesterone on adult cardiac regeneration were analysed.

Results: Progesterone supplementation enhanced cardiomyocyte proliferation in a progesterone receptor-dependent manner. Progesterone up-regulated YAP expression and knockdown of YAP by small interfering RNA reduced progesterone-mediated cardiomyocyte proliferative effect. Progesterone receptor interacted with the YAP promoter, determined by ChIP and EMSA; progesterone increased luciferase activity of YAP promoter and up-regulated YAP target genes. Progesterone administration also promoted adult cardiomyocyte proliferation and improved cardiac function in myocardial infarction.

Conclusion: Our data uncover a role of circulating progesterone withdrawal as a novel mechanism for the postnatal loss of mammalian cardiac regenerative potential. Progesterone promotes both neonatal and adult cardiomyocyte proliferation by up-regulating YAP expression.
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http://dx.doi.org/10.1111/cpr.12910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653240PMC
November 2020

GRK4-mediated adiponectin receptor-1 phosphorylative desensitization as a novel mechanism of reduced renal sodium excretion in hypertension.

Clin Sci (Lond) 2020 09;134(18):2453-2467

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.

Hypertensive patients have impaired sodium excretion. However, the mechanisms are incompletely understood. Despite the established association between obesity/excess adiposity and hypertension, whether and how adiponectin, one of the adipokines, contributes to impaired sodium excretion in hypertension has not been previously investigated. The current study tested the hypothesis that adiponectin promotes natriuresis and diuresis in the normotensive state. However, impaired adiponectin-mediated natriuresis and diuresis are involved in pathogenesis of hypertension. We found that sodium excretion was reduced in adiponectin knockout (Adipo-/-) mice; intrarenal arterial infusion of adiponectin-induced natriuresis and diuresis in Wistar-Kyoto (WKY) rats. However, the natriuretic and diuretic effects of adiponectin were impaired in spontaneously hypertensive rats (SHRs), which were ascribed to the hyperphosphorylation of adiponectin receptor and subsequent uncoupling from Gαi. Inhibition of adiponectin receptor phosphorylation by a specific point mutation restored its coupling with Gαi and the adiponectin-mediated inhibition of Na+-K+-ATPase activity in renal proximal tubule (RPT) cells from SHRs. Finally, we identified G protein-coupled receptor kinase 4 (GRK4) as a mediator of adiponectin receptor hyperphosphorylation; mice transgenic for a hyperphosphorylating variant of GRK4 replicated the abnormal adiponectin function observed in SHRs, whereas down-regulation of GRK4 by renal ultrasound-directed small interfering RNA (siRNA) restored the adiponectin-mediated sodium excretion and reduced the blood pressure in SHRs. We conclude that the stimulatory effect of adiponectin on sodium excretion is impaired in hypertension, which is ascribed to the increased renal GRK4 expression and activity. Targeting GRK4 restores impaired adiponectin-mediated sodium excretion in hypertension, thus representing a novel strategy against hypertension.
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http://dx.doi.org/10.1042/CS20200671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654732PMC
September 2020

IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4.

Nat Commun 2020 09 16;11(1):4664. Epub 2020 Sep 16.

Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, China.

Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.
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http://dx.doi.org/10.1038/s41467-020-18519-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494935PMC
September 2020

AdipoRon, an adiponectin receptor agonist, protects contrast-induced nephropathy by suppressing oxidative stress and inflammation via activation of the AMPK pathway.

Clin Exp Nephrol 2020 Nov 30;24(11):989-998. Epub 2020 Jul 30.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.

Background: Contrast-induced nephropathy (CIN), a complication caused by using contrast medium during diagnostic and interventional procedures, occurs frequently and lacks effective treatment. AdipoRon, the agonist of adiponectin receptors, has been shown to benefit many organs including the kidney. This study aimed to investigate the role of AdipoRon in treating CIN.

Methods: CIN model was established via infusing iopromide (1.8 g/kg) in Sprague-Dawley (SD) rats; NRK52E cells were treated with iopromide (5-50 μM). Renal function, renal histopathology, levels of lactate dehydrogenase (LDH) release, cell vitality, oxidative stress and inflammatory markers were measured to evaluate the protective effects of AdipoRon. The level of pAMPK/AMPK was determined by western blot.

Results: AdipoRon (50 mg/kg) significantly reversed serum creatinine, blood urea nitrogen, creatinine clearance and urinary kidney injury molecule-1 levels induced by iopromide in SD rats. Besides, it decreased the renal injury score and apoptosis of renal cells. AdipoRon also reversed the changes of antioxidant markers, pro-oxidant and inflammatory markers induced by iopromide. Moreover, the in vitro studies showed that AdipoRon decreased LDH release and increased cell vitality in NRK52E cells treated with iopromide. Then, we demonstrated that the protection of AdipoRon was accompanied by augmented AMPK phosphorylation. Both in vivo and in vitro studies demonstrated that compound c, an AMPK inhibitor, reversed the AdipoRon-mediated improvement in the CIN model.

Conclusion: Our data indicate that AdipoRon protects against the CIN by suppressing oxidative stress and inflammation via activating the AMPK pathway, showing that AdipoRon might be a potential candidate for the prevention and therapy of CIN.
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http://dx.doi.org/10.1007/s10157-020-01944-2DOI Listing
November 2020

The cumulative blood pressure load and target organ damage in patients with essential hypertension.

J Clin Hypertens (Greenwich) 2020 06 19;22(6):981-990. Epub 2020 May 19.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

The area under the blood pressure curve is associated with target organ damage, but accurately estimating its value is challenging. This study aimed to improve the utility of the area under the blood pressure curve to predict hypertensive target organ damage. This retrospective cohort study comprised of 634 consecutive patients with essential hypertension for >1 year. Target organ damage was defined as the presence of left ventricular hypertrophy and/or carotid artery plaques. We evaluated the associations between the cumulative blood pressure load, which was derived from ambulatory blood pressure monitoring data, and target organ damage. The predictive value of the cumulative blood pressure load for target organ damage was assessed using receiver operating characteristic curves. Left ventricular hypertrophy and carotid artery plaques were present in 392 (61.8%) and 316 (49.8%) patients, respectively. Patients with left ventricular hypertrophy and/or carotid artery plaques had higher 24-hour blood pressure, nocturnal cumulative systolic blood pressure, and nocturnal cumulative pulse pressure load. The nocturnal cumulative systolic blood pressure load was an independent predictor of left ventricular hypertrophy (odds ratio = 1.002, 95% confidence interval: 1.001-1.004; P = .000) and carotid artery plaques (odds ratio = 1.003, 95% confidence interval: 1.002-1.007; P = .007). The nocturnal cumulative systolic blood pressure and cumulative pulse pressure load, relative to mean blood pressure, were superior in predicting hypertensive target organ damage. Hence, the cumulative blood pressure load is a better indicator of blood pressure consequences, and the nocturnal cumulative systolic blood pressure and cumulative pulse pressure loads could predict target organ damage.
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http://dx.doi.org/10.1111/jch.13875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384193PMC
June 2020

Elevated Salt Taste Threshold Is Associated with Increased Risk of Coronary Heart Disease.

J Cardiovasc Transl Res 2020 12 6;13(6):1016-1023. Epub 2020 May 6.

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.

High salt intake has been associated with coronary heart disease (CHD). The salt taste threshold could affect the salt intake, but its role in CHD is uncertain. We studied the association of salt taste threshold with CHD. In this study, the levels of salt detection threshold, recognition threshold, and taste preference were higher in CHD than in controls. The salt taste recognition threshold was significantly associated with CHD, and the significant association persisted after adjustment for traditional risk factors. Individuals with high level of salt taste recognition threshold were at a greater risk of CHD. Coincident occurrence of high level of salt taste recognition threshold, hypertension, and diabetes increased the risk of CHD. Thus, a high level of salt taste recognition threshold increases the risk of CHD, and the concurrence of high level of salt taste recognition threshold, hypertension, and diabetes further increases the risk of CHD.
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http://dx.doi.org/10.1007/s12265-020-10017-4DOI Listing
December 2020
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