Dendropanax morbifera Prevents Cardiomyocyte Hypertrophy by Inhibiting the Sp1/GATA4 Pathway

An extract of Dendropanax morbifera branch exerts antioxidant, anti-inflammatory, antithrombotic, and anticancer activities. The purpose of this study was to investigate the effect of the extract in isoproterenol-induced cardiac hypertrophy. Phalloidin staining showed that treatment with the extract dramatically prevents isoproterenol-induced H9c2 cell enlargement and the expression of cardiac hypertrophic marker genes, including atrial natriuretic peptide (ANP) and B-type brain natriuretic peptide (BNP). Further, pretreatment with the extract decreased isoproterenol-induced GATA4 and Sp1 expression in H9c2 cells. Overexpression of Sp1 induced the expression of GATA4. The forced expression of Sp1 or its downstream target GATA4, as well as the co-transfection of Sp1 and GATA4 increased the expression of ANP, which was decreased by treatment with the extract. To further elucidate the regulation of the Sp1/GATA4-mediated expression of ANP, knockdown experiments were performed. Transfection with small interfering RNAs (siRNAs) for Sp1 or GATA4 decreased ANP expression. The extract did not further inhibit the expression of ANP reduced by the transfection of GATA4 siRNA. Sp1 knockdown did not affect the expression of ANP that was induced by the overexpression of GATA4; however, GATA4 knockdown abolished the expression of ANP that had been induced by Sp1 overexpression. The extract treatment also attenuated the isoproterenol-induced activation of p38 MAPK, ERK1/2, and JNK1. Hesperidin, catechin, 2,5-dihydroxybenzoic acid, and salicylic acid are the main phenolic compounds present in the extract as observed by high performance liquid chromatography. Hesperidin and 2,5-dihydroxybenzoic acid attenuated isoproterenol-induced cardiac hypertrophy. These findings suggest that the D. morbifera branch extract prevents cardiac hypertrophy by downregulating the activation of Sp1/GATA4 and MAPK signaling pathways.

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Carboxypeptidase A4 promotes cardiomyocyte hypertrophy through activating PI3K-AKT-mTOR signaling

Bioscience Reports ◽

10.1042/bsr20200669 ◽

2020 ◽

Vol 40 (5) ◽

Author(s):

Weinian Gao ◽

Na Guo ◽

Shuguang Zhao ◽

Ziying Chen ◽

Wenli Zhang ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Cancer Biology ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Marker Genes ◽

Mechanism Study ◽

Rat Cardiomyocytes

Abstract Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. Current studies have identified the roles of CPA4 in cancer biology and insulin sensitivity. However, the roles of CPA4 in other diseases are not known. In the present study, we investigated the roles of CPA4 in cardiac hypertrophy. The expression of CPA4 was significantly increased in the hypertrophic heart tissues of human patients and isoproterenol (ISO)-induced hypertrophic heart tissues of mice. We next knocked down Cpa4 with shRNA or overexpressed Cpa4 using adenovirus in neonatal rat cardiomyocytes and induced cardiomyocyte hypertrophy with ISO. We observed that Cpa4 overexpression promoted whereas Cpa4 knockdown reduced ISO-induced growth of cardiomyocyte size and overexpression of hypertrophy marker genes, such as myosin heavy chain β (β-Mhc), atrial natriuretic peptide (Anp), and brain natriuretic peptide (Bnp). Our further mechanism study revealed that the mammalian target of rapamycin (mTOR) signaling was activated by Cpa4 in cardiomyocytes, which depended on the phosphoinositide 3-kinase (PI3K)-AKT signaling. Besides, we showed that the PI3K-AKT-mTOR signaling was critically involved in the roles of Cpa4 during cardiomyocyte hypertrophy. Collectively, these results demonstrated that CPA4 is a regulator of cardiac hypertrophy by activating the PI3K-AKT-mTOR signaling, and CPA4 may serve as a promising target for the treatment of hypertrophic cardiac diseases.

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Betulinic Acid Protects DOX-Triggered Cardiomyocyte Hypertrophy Response through the GATA-4/Calcineurin/NFAT Pathway

Molecules ◽

10.3390/molecules26010053 ◽

2020 ◽

Vol 26 (1) ◽

pp. 53

Author(s):

Jung Joo Yoon ◽

Chan Ok Son ◽

Hye Yoom Kim ◽

Byung Hyuk Han ◽

Yun Jung Lee ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Betulinic Acid ◽

Cardiomyocyte Hypertrophy ◽

Ros Generation ◽

H9c2 Cells ◽

Myosin Light Chain 2 ◽

Cardiovascular Morbidity And Mortality

Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 µM) in the presence or absence of BA (0.1–1 μM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (β-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 µM. DOX-induced activation of GATA-4 and calcineurin/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.

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Effect of AT2 blockade on cardiac hypertrophy as induced by high dietary salt in the proatrial natriuretic peptide (ANP) gene-disrupted mouse

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y06-016 ◽

2006 ◽

Vol 84 (6) ◽

pp. 625-634 ◽

Cited By ~ 3

Author(s):

Ekaterini Angelis ◽

M. Yat Tse ◽

Michael A. Adams ◽

Stephen C. Pang

Keyword(s):

Extracellular Matrix ◽

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Transforming Growth Factor ◽

Matrix Metalloproteinase 2 ◽

Marker Genes ◽

Type I ◽

Dietary Salt ◽

Tissue Mass ◽

Extracellular Matrix Components

The role of the angiotensin II type 2 receptor (AT2) during alterations in cardiac size remains largely unclear. Through employment of an AT2 antagonist, the present study explored a possible involvement of the AT2 receptor during salt-induced cardiac hypertrophy in the proatrial natriuretic peptide gene-disrupted mouse (ANP−/−). ANP−/− mice received either saline solution or the AT2 antagonist, PD123319, and were then placed on a high salt diet (8.0% NaCl) for 3 weeks. Cardiac and pulmonary size, expression of the renin–angiotensin system (RAS), and the behaviour of various hypertrophy marker genes were assessed. PD123319 caused enhanced expression of the systemic RAS, yet the cardiac RAS was largely unaffected. Although AT2 blockade did not alter whole cardiac mass, right ventricle mass, as well as pulmonary mass-to-body mass ratios were significantly decreased. Collagen type I was decreased in the latter tissues, likely contributing to the regression in mass. Several players essential in the maintenance of myocardial extracellular matrix homeostasis including B-type natriuretic peptide, matrix metalloproteinase-2, tumour necrosis factor, and transforming growth factor were also significantly altered by PD123319. These data suggest that AT2 blockade is involved in significant changes in myocardial extracellular matrix components translating into decreases in tissue mass in the salt-sensitive ANP−/− animal.

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JMJD1A Represses the Development of Cardiomyocyte Hypertrophy by Regulating the Expression of Catalase

BioMed Research International ◽

10.1155/2020/5081323 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Rongjia Zang ◽

Qingyun Tan ◽

Fanrong Zeng ◽

Dongwei Wang ◽

Shuang Yu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Dependent Manner ◽

Oxygen Species ◽

Mechanism Study ◽

Aortic Constriction ◽

Rat Cardiomyocytes ◽

Protein Levels

The histone demethylase JMJD family is involved in various physiological and pathological functions. However, the roles of JMJD1A in the cardiovascular system remain unknown. Here, we studied the function of JMJD1A in cardiac hypertrophy. The mRNA and protein levels of JMJD1A were significantly downregulated in the hearts of human patients with hypertrophic cardiomyopathy and the hearts of C57BL/6 mice underwent cardiac hypertrophy induced by transverse aortic constriction (TAC) surgery or isoproterenol (ISO) infusion. In neonatal rat cardiomyocytes (NRCMs), siRNA-mediated JMJD1A knockdown facilitated ISO or angiotensin II-induced increase in cardiomyocyte size, protein synthesis, and expression of hypertrophic fetal genes, including atrial natriuretic peptide (Anp), brain natriuretic peptide (Bnp), and Myh7. By contrast, overexpression of JMJD1A with adenovirus repressed the development of ISO-induced cardiomyocyte hypertrophy. We observed that JMJD1A reduced the production of total cellular and mitochondrial levels of reactive oxygen species (ROS), which was critically involved in the effects of JMJD1A because either N-acetylcysteine or MitoTEMPO treatment blocked the effects of JMJD1A deficiency on cardiomyocyte hypertrophy. Mechanism study demonstrated that JMJD1A promoted the expression and activity of Catalase under basal condition or oxidative stress. siRNA-mediated loss of Catalase blocked the protection of JMJD1A overexpression against ISO-induced cardiomyocyte hypertrophy. These findings demonstrated that JMJD1A loss promoted cardiomyocyte hypertrophy in a Catalase and ROS-dependent manner.

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Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.748156 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ran Xu ◽

Le Kang ◽

Siang Wei ◽

Chunjie Yang ◽

Yuanfeng Fu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Pressure Overload ◽

Protective Role ◽

Cardiomyocyte Hypertrophy ◽

Marker Genes ◽

Autophagic Flux ◽

Ang Ii ◽

Neonatal Cardiomyocytes ◽

Primary Mouse

Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

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Anacardic acid protects against phenylephrine-induced mouse cardiac hypertrophy through JNK signaling-dependent regulation of histone acetylation

10.1101/2020.02.06.937672 ◽

2020 ◽

Author(s):

Bohui Peng ◽

Chang Peng ◽

Xiaomei Luo ◽

Lixin Huang ◽

Qian Mao ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Histone Acetylation ◽

Mapk Pathway ◽

Mapk Signaling ◽

Anacardic Acid ◽

Mitogen Activated Protein Kinase ◽

Cardiomyocyte Hypertrophy ◽

Jnk Signaling ◽

Hat Inhibitor

AbstractCardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetylase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling in cardiac hypertrophy. A mouse model of cardiomyocyte hypertrophy was successfully established in vitro using PE. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9 hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and β-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiac hypertrophy. In particular, AA inhibits the effects of JNK signaling on HAT-mediated histone acetylation, and could therefore be used to prevent and treat hypertrophic cardiomyopathy.

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5-Aminolevulinic acid combined with sodium ferrous citrate ameliorates H2O2-induced cardiomyocyte hypertrophy via activation of the MAPK/Nrf2/HO-1 pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00369.2014 ◽

2015 ◽

Vol 308 (8) ◽

pp. C665-C672 ◽

Cited By ~ 20

Author(s):

Mingyi Zhao ◽

Huiming Guo ◽

Jimei Chen ◽

Masayuki Fujino ◽

Hidenori Ito ◽

...

Keyword(s):

Oxidative Stress ◽

Natriuretic Peptide ◽

Aminolevulinic Acid ◽

Cardiomyocyte Hypertrophy ◽

Marker Genes ◽

Heme Oxygenase 1 ◽

Dependent Manner ◽

Ros Production ◽

Ferrous Citrate ◽

Atrial Natriuretic

Hydrogen peroxide (H2O2) causes cell damage via oxidative stress. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that can protect cardiomyocytes against oxidative stress. In this study, we investigated whether the heme precursor 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) could protect cardiomyocytes from H2O2-induced hypertrophy via modulation of HO-1 expression. HL-1 cells pretreated with/without 5-ALA and SFC were exposed to H2O2 to induce a cardiomyocyte hypertrophy model. Hypertrophy was evaluated by planar morphometry, 3H-leucine incorporation, and RT-PCR analysis of hypertrophy-related gene expressions. Reactive oxygen species (ROS) production was assessed by 5/6-chloromethyl-2′,7′-ichlorodihydrofluorescein diacetate acetylester. HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expressions were analyzed by Western blot. In our experiments, HL-1 cells were transfected with Nrf2 siRNA or treated with a signal pathway inhibitor. We found several results. 1) ROS production, cell surface area, protein synthesis, and expressions of hypertrophic marker genes, including atrial natriuretic peptide, brain natriuretic peptide, atrial natriuretic factor, and β-myosin heavy chain, were decreased in HL-1 cells pretreated with 5-ALA and SFC. 2) 5-ALA and SFC increased HO-1 expression in a dose- and time-dependent manner, associated with upregulation of Nrf2. Notably, Nrf2 siRNA dramatically reduced HO-1 expression in HL-1 cells. 3) ERK1/2, p38, and SAPK/JNK signaling pathways were activated and modulate 5-ALA- and SFC-enhanced HO-1 expression. SB203580 (p38 kinase), PD98059 (ERK), or SP600125 (JNK) inhibitors significantly reduced this effect. In conclusion, our data suggest that 5-ALA and SFC protect HL-1 cells from H2O2-induced cardiac hypertrophy via activation of the MAPK/Nrf2/HO-1 signaling pathway.

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Na+/H+ exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase

Physiological Genomics ◽

10.1152/physiolgenomics.00133.2017 ◽

2018 ◽

Vol 50 (5) ◽

pp. 332-342 ◽

Cited By ~ 4

Author(s):

Nabeel Abdulrahman ◽

Beatrice Jaspard-Vinassa ◽

Larry Fliegel ◽

Aayesha Jabeen ◽

Sadaf Riaz ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Internal Diameter ◽

S6 Kinase ◽

Cardiac Phenotype ◽

P90 Ribosomal S6 Kinase ◽

Ribosomal S6 Kinase

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.

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Abstract 352: Dual Specificity Phosphatase 8 (dusp8) Regulates Cardiac Remodeling and Function by Affecting Erk1/2 Phosphorylation

Circulation Research ◽

10.1161/res.117.suppl_1.352 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Ruijie Liu ◽

Jeffery Molkentin

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Structure Function ◽

Mapk Signaling ◽

Marker Genes ◽

Cardiac Structure ◽

Mapk Phosphorylation ◽

Erk Phosphorylation ◽

Dual Specificity

Rationale: Mitogen-activated protein kinases (MAPKs) are activated in the heart by various stress-inducing stimuli, where they participate in cardiac hypertrophy, contractility, and cell death. A family of dual-specificity phosphatases (DUSPs) directly inactivates each of the MAPK terminal effectors, thus providing a feedback mechanism to regulate the activity and recycling of MAPKs. How DUSPs regulate MAPK signaling to influence cardiac function is not well understood. Objective: To determine the role of DUSP8 in regulating MAPK signaling and the effect on cardiac disease. Methods and Results: We generated DUSP8 null (KO) and inducible cardiac specific DUSP8 transgenic mice to assess the effect on cardiac structure-function at baseline and with stress-responsiveness. Loss of DUSP8 did not alter cardiac structure-function or MAPK phosphorylation at baseline. However, with pressure overload or myocardial infarction injury, DUSP8 KO mice developed concentric hypertrophy with preserved cardiac function compared to wild type controls, suggesting a cardioprotective role for loss of DUSP8. DUSP8 transgenic mice developed cardiac hypertrophy at baseline as evidenced by elevated expression of hypertrophic marker genes as well as increased heart weights and cross sectional area of the myocytes. DUSP8 transgenic mice also had mild interstitial fibrosis and reduced fractional shortening. Biochemical analysis of MAPK phosphorylation demonstrated increased ERK phosphorylation in KO mice upon stress, suggesting a molecular mechanism underlying the increased concentric growth of DUSP8 KO cardiomyocytes. Conclusions: Taken together, these data demonstrate that DUSP8 modulates ERK phosphorylation to influence cardiomyocyte growth and consequent cardiac function with injury. Further analysis of MAPK phosphorylation in DUSP8 transgenic mice will provide more insight into DUSP8-ERK signaling in the heart.

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JNK signaling-dependent regulation of histone acetylation are involved in anacardic acid alleviates cardiomyocyte hypertrophy induced by phenylephrine

PLoS ONE ◽

10.1371/journal.pone.0261388 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261388

Author(s):

Bohui Peng ◽

Chang Peng ◽

Xiaomei Luo ◽

Shuqi Wu ◽

Qian Mao ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Histone Acetylation ◽

Mapk Pathway ◽

Mapk Signaling ◽

Anacardic Acid ◽

Mitogen Activated Protein Kinase ◽

Cardiomyocyte Hypertrophy ◽

Jnk Signaling ◽

Hat Inhibitor

Cardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetyltransferase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the related upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling pathway in cardiac hypertrophy induced by PE. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9ac hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and β-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiomyocyte hypertrophy. In particular, AA inhibits the effects of JNK signaling on HATs-mediated histone acetylation, and could therefore be used to prevent and treat pathological cardiac hypertrophy.

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