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The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

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Acta Pharmaceutica Sinica B 2021年第5期11卷 1286-1299页

作者： Zhenzhen Li Zhen Guo Rui Lan Sidong Cai Zhirong Lin Jingyan Li Junjian Wang Zhuoming Li Peiqing Liu Department of Pharmacology and Toxicology School of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510006China Center for Cardiovascular Research and Division of Cardiology Washington University School of MedicineSt.LouisMO 63101USA International Institute for Translational Chinese Medicine School of Pharmaceutical SciencesGuangzhou University of Chinese MedicineGuangzhou 510006China

The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac ***4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription *** present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac ***4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac ***1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac ***4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 *** of BRD4 and PARP1 were observed by coimmunoprecipitation and *** of BRD4 induced by PARP1 was investigated by PARylation *** response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and *** investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of *** of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic *** present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

关键词： BRD4 PARP1 PARylation Isoproterenol cardiac hypertrophy RNA Pol II Transcription activation Hypertrophic genes

lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α–mitochondrial complexⅣaxis

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Frontiers of Medicine 2024年第4期18卷 664-677页

作者： Tong Yu Qiang Gao Guofang Zhang Tianyu Li Xiaoshan Liu Chao Li Lan Zheng Xiang Sun Jianbo Wu Huiying Cao Fangfang Bi Ruifeng Wang Haihai Liang Xuelian Li Yuhong Zhou Lifang Lv Hongli Shan Department of Physiology School of Basic MedicineHarbin Medical UniversityHarbin150081China State Key Laboratory of Frigid Zone Cardiovascular Disease Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China Key Laboratory of Cardiovascular Research Ministry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China The Center of Functional Experiment Teaching School of Basic MedicineHarbin Medical UniversityHarbin150081China

Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial *** roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplored in this ***,a previously unknown lncRNA,Gm20257,was *** markedly increased under hypertrophic stress in vivo and in *** suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte ***,the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensinⅡ-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively,thus restoring cardiac ***,Gm20257 restored mitochondrial complexⅣlevel and enhanced mitochondrial *** prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1(PGC-1α),which could increase mitochondrial complex ***,Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α.Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1αwas a direct downstream target of *** interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial *** findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complexⅣaxis,offering a novel approach for attenuating pathological cardiac hypertrophy.

关键词： lncRNA Gm20257 cardiac hypertrophy PGC-1α mitochondrial complexⅣ ATP

Decorin Induces cardiac hypertrophy by Regulating the CaMKⅡ/MEF-2 Signaling Pathway In Vivo

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Current Medical Science 2021年第5期41卷 857-862页

作者： Yan YANG Wei-wei YU Wen YAN Qin XIA Department of Geriatrics Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Objective:cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart *** hypertrophy is mostly considered reversible,and recent studies have indicated that decorin not only prevents cardiac fibrosis associated with hypertension,but also achieves therapeutic effects by blocking fibrosis-related signaling ***,the mechanism of action of decorin remains unknown and ***:We determined the degree of myocardial hypertrophy by measuring the ratios of the heart weight/body weight and left ventricular weight/body weight,histological analysis and *** blotting was performed to detect the expression levels of CaMKⅡ,p-CaMKⅡ and MEF-2 in the ***:Our results confirmed that decorin can regulate the CaMKⅡ/MEF-2 signaling pathway,with inhibition thereof being similar to that of decorin in reducing cardiac ***:Taken together,the results of the present study showed that decorin induced cardiac hypertrophy by regulating the CaMKⅡ/MEF-2 signaling pathway in vivo,revealing a new therapeutic approach for the prevention of cardiac hypertrophy.

关键词： decorin cardiac hypertrophy calcium/calmodulin-dependent protein kinaseⅡ myocyte enhancer factor 2 atrial natriuretic peptide

Alterations in gut microbiota and metabolites associated with altitude-induced cardiac hypertrophy in rats during hypobaric hypoxia challenge

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Science China(Life Sciences) 2022年第10期65卷 2093-2113页

作者： Zhiyuan Pan Yichen Hu Zongyu Huang Ni Han Yan Li Xiaomei Zhuang Jiye Yin Hui Peng Quansheng Gao Wenpeng Zhang Yong Huang Yujun Cui Yujing Bi Zhenjiang Zech Xu Ruifu Yang State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and EpidemiologyBejing 10o071China State Key Laboratory of Food Science and Technology Nanchang UniversityNanchang 330047China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBejing 100850China Tianjin Institute of Environmental&Operational Medicine Tianjin 300050China Microbiome Medicine Center Department of Laboratory MedicineZhujiang HospitalSouthern Medical UniversityGuangzhou510280China

The gut microbiota is involved in host responses to high ***,the dynamics of intestinal microecology and their association with altitude-related illness are poorly ***,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 *** identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and *** aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ***-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia ***,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic *** results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia *** in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.

关键词： high altitude gut microbiota short-chain fatty acids bile acids hypobaric hypoxia cardiac hypertrophy

lncRNA ZNF593-AS inhibits cardiac hypertrophy and myocardial remodeling by upregulating Mfn2 expression

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Frontiers of Medicine 2024年第3期18卷 484-498页

作者： Xiang Nie Jiahui Fan Yanwen Wang Rong Xie Chen Chen Huaping Li Dao Wen Wang Division of Cardiology Department of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan430030China

lncRNA ZNF593 antisense(ZNF593-AS)transcripts have been implicated in heart failure through the regulation of myocardial *** decreased transcriptional activity of ZNF593-AS has also been detected in cardiac ***,the function of ZNF593-AS in cardiac hypertrophy remains ***,we report that the expression of ZNF593-AS reduced in a mouse model of left ventricular hypertrophy and cardiomyocytes in response to treatment with the hypertrophic agonist phenylephrine(PE).In vivo,ZNF593-AS aggravated pressure overload–induced cardiac hypertrophy in knockout *** contrast,cardiomyocyte-specific transgenic mice(ZNF593-AS MHC-Tg)exhibited attenuated TAC-induced cardiac *** vitro,vector-based overexpression using murine or human ZNF593-AS alleviated PE-induced myocyte hypertrophy,whereas GapmeR-induced inhibition aggravated hypertrophic *** using RNA-seq and gene set enrichment analyses,we identified a link between ZNF593-AS and oxidative phosphorylation and found that mitofusin 2(Mfn2)is a direct target of ***593-AS exerts an antihypertrophic effect by upregulating Mfn2 expression and improving mitochondrial ***,it represents a promising therapeutic target for combating pathological cardiac remodeling.

关键词： lncRNA ZNF593-AS cardiac hypertrophy Mfn2 oxidative phosphorylation

Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling

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Frontiers of Medicine 2015年第4期9卷 444-456页

作者： Samuel Chege Gitau Xuelian Li Dandan Zhao Zhenfeng Guo Haihai Liang Ming Qian Lifang Lv Tianshi Li Bozhi Xu Zhiguo Wang Yong Zhang Chaoqian Xu Yanjie Lu Zhiming Du Hongli Shan Baofeng Yang Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China Key Laboratory of Cardiovascular Research Ministry of Education) Harbin Medical University Harbin 150081 China Institute of Cardiovascular Research Harbin Medical University Harbin 150081 China Department of Pharmacy and Complementary Medicine School of Health Sciences Kenyatta University PO. BOX 43844-00100 Nairobi Kenya Institute of Clinical Pharmacy the Second Affiliated Hospital Harbin Medieal University Harbin 150081 China

Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid （aspirin） provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction （TAC） or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin （10 mg·kg^-1· d^-1）; the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II （10 nmol· L^-1） was treated with the human equivalent of low （10 or 100μmol·L^-1） and high （1000μmol·L^-1） aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, p-myosin heavy chain （IS-MHC）, atrial natriuretic peptide （ANP）, and b-type natriuretic peptide （BNP）. Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3~. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.

关键词： aspirin Akt cardiac hypertrophy GSK-3β Wnt/β-catenin

Familial Atrial Enlargement,Conduction Disorder and Symmetric cardiac hypertrophy Are Early Signs of PRKAG2 R302Q

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Current Medical Science 2020年第3期40卷 486-492页

作者： Jing HU Ben TANG Jing WANG Kun HUANG Yan WANG Shuai LU Hnkeshsing Baboo Gowreesunkur Ya WANG Di Wu Henry Anselmo Mayala Zhao-hui WANG Department of Cardiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China First Clinical School Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Radiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Key Laboratory of Molecular Imaging of Hubei Province Wuhan430022China

PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial *** can also lead to serious consequences,such as sudden *** the genetic and clinical heterogeneity makes the early diagnosis of PS *** we studied a family with familial hypertrophic cardiomyopathy and other diverse *** analysis identified a missense mutation(Arg302Gln)in the five affected subjects of the *** electrocardiograph performance of the five was composed of sinus bradycardia(SB),WPWs,right bundle branch block(RBBB),atrioventricular block(AVB),left bundle branch block(LBBB),supraventricular tachycardia(SVT)and atrial premature beat(APB).Among them,the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old;two members progressed over time to serious conduction damage,and the proband received a pacemaker at the age of 27 due to ***,according to cardiac magnetic resonance and echocardiography,the youngest one showed symmetric hypertrophy;three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy;all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier *** conclusion,the conduction system disorder,familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.

关键词： arrhythmia atrial enlargement cardiac hypertrophy PRKAG2 syndrome R302Q mutation

cardiac hypertrophy is Positively Regulated by MicroRNA-24 in Rats

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Chinese Medical Journal 2018年第11期131卷 1333-1341页

作者： Juan Gao Min Zhu Rui-Feng Liu Jian-Shu Zhang Ming Xu Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Ministry of Health Key Laboratory of Molecular Cardiovascular Science Ministry of Education Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191 China

Background： MicroRNA-24 （miR-24） plays an important role in heart failure by reducing the efficiency of myocardial excitation-contraction coupling. Prolonged cardiac hypertrophy may lead to heart failure, but little is known about the role of miR-24 in cardiac hypertrophy. This study aimed to preliminarily investigate the function of miR-24 and its mechanisms in cardiac hypertrophy. Methods： Twelve Sprague-Dawley rats with a body weight of 50 ± 5 g were recruited and randonlly divided into two groups： a transverse aortic constriction （TAC） group and a sham surgery group. hypertrophy index was measured and calculated by echocardiography and hematoxylin and eosin staining. TargetScans algorithm-based prediction was used to search for the targets of miR-24, which was subsequently confirmed by a real-time polymerase chain reaction and luciferase assay, lmmunofluorescence labeling was used to measure the cell surface area, and 3H-leucine incorporation was used to detect the synthesis of total protein in neonatal rat cardiac myocytes （NRCMs） with the overexpression of miR-24. In addition, flow cytometry was performed to observe the alteration in the cell cycle. Statistical analysis was carried out with GraphPad Prism v5.0 and SPSS 19.0. A two-sided P 〈 0.05 was considered as the threshold for significance. Results： The expression of miR-24 was abnormally increased in TAC rat cardiac tissue （ t =-2.938, P 〈 0.05）. TargetScans algorithm-based prediction demonstrated that CDKN 1B （p27, Kip 1 ）, a cell cycle regulator, was a putative target of miR-24, and was confirmed by luci ferase assay. The expression of p27 was decreased in TAC rat cardiac tissue （t = 2.896, P 〈 0.05）. The overexpression of miR-24 in NRCMs led to the decreased expression of p27 （t = 4.400, P 〈 0.01 ）, and decreased G0/G 1 arrest in cell cycle and cardiomyocylc hypertrophy. Conclusion： MiR-24 promotes cardiac hypertrophy partly by affecting the cell cycle through down-regulation of p27 expression.

关键词： cardiac hypertrophy Cell Cycle MicroRNA MicroRNA-24 p27

L-carvone attenuates myocardial injury and dyslipidemia in rats with isoproterenol-induced cardiac hypertrophy

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Asian Pacific Journal of Tropical Biomedicine 2023年第1期13卷 17-25页

作者： Anitha Nagarajan Victor Arokia Doss Department of Biochemistry PSG College of Arts and ScienceCoimbatore-641014Tamil NaduIndia

Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata *** extracts against isoproterenol-induced cardiac hypertrophy in ***:Isoproterenol(5 mg/kg)was injected intraperitoneally into rats for one month to induce cardiac hypertrophy.L-carvone(25 and 100 mg/kg)was administered orally to treat cardiac *** cardioprotective activity of L-carvone was evaluated by electrocardiogram,histopathological analysis as well as determination of biochemical parameters and enzymatic ***:L-carvone from Mentha spicata *** 25 and 100 mg/kg ameliorated isoproterenol-induced cardiac hypertrophy,as evidenced by reduced QRS interval on electrocardiogram,and decreased heart weight and heart *** addition,both doses of L-carvone markedly lowered the levels of glucose,total protein,low-density lipoprotein cholesterol,aspartate transaminase,alanine transaminase,lactate dehydrogenase,creatine kinase MB,troponin-Ⅰ,N-terminal pro-B type natriuretic peptide and triglycerides while increasing high-density lipoprotein cholesterol and lipase level(Pcardiac histoarchitecture of rats with isoproterenol-induced cardiac ***:L-carvone from Mentha spicata *** extract can restore abnormal cardiac function and may be further explored as a therapeutic agent against the deleterious effects of cardiac hypertrophy after further evaluation.

关键词： cardiac hypertrophy L-carvone Dyslipidemia Myocardial injury Isoproterenol Mentha spicata