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

Molecules ◽  
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.

scholarly journals Hispidulin Attenuates Cardiac Hypertrophy by Improving Mitochondrial Dysfunction

2020 ◽  
Vol 7 ◽  
Author(s):  
Yan Wang ◽  
Zengshuo Xie ◽  
Nan Jiang ◽  
Zexuan Wu ◽  
Ruicong Xue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Mitochondrial Function ◽  
Specific Inhibitor ◽  
Cardiomyocyte Hypertrophy ◽  
Mitochondrial Morphology ◽  
Protective Effects

Cardiac hypertrophy is a pathophysiological response to harmful stimuli. The continued presence of cardiac hypertrophy will ultimately develop into heart failure. The mitochondrion is the primary organelle of energy production, and its dysfunction plays a crucial role in the progressive development of heart failure from cardiac hypertrophy. Hispidulin, a natural flavonoid, has been substantiated to improve energy metabolism and inhibit oxidative stress. However, how hispidulin regulates cardiac hypertrophy and its underlying mechanism remains unknown. We found that hispidulin significantly inhibited pressure overload-induced cardiac hypertrophy and improved cardiac function in vivo and blocked phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. We further proved that hispidulin remarkably improved mitochondrial function, manifested by increased electron transport chain (ETC) subunits expression, elevated ATP production, increased oxygen consumption rates (OCR), normalized mitochondrial morphology, and reduced oxidative stress. Furthermore, we discovered that Sirt1, a well-recognized regulator of mitochondrial function, might be a target of hispidulin, as evidenced by its upregulation after hispidulin treatment. Cotreatment with EX527 (a Sirt1-specific inhibitor) and hispidulin nearly completely abolished the antihypertrophic and protective effects of hispidulin on mitochondrial function, providing further evidence that Sirt1 could be the pivotal downstream effector of hispidulin in regulating cardiac hypertrophy.

scholarly journals AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Anca Remes ◽  
Andreas H. Wagner ◽  
Nesrin Schmiedel ◽  
Markus Heckmann ◽  
Theresa Ruf ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Activated T Cells ◽  
Specific Expression ◽  
Adult Mice ◽  
Before And After ◽  
A Cell

AbstractPrevious studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

scholarly journals LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shi Peng ◽  
Xiao-feng Lu ◽  
Yi-ding Qi ◽  
Jing Li ◽  
Juan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

scholarly journals Rap1GAP Mediates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Inhibiting Autophagy and Increasing Oxidative Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Yan Gao ◽  
Di Zhao ◽  
Wen-zhi Xie ◽  
Tingting Meng ◽  
Chunxiao Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Generation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Neonatal Cardiomyocytes ◽  
And Oxidative Stress

Abnormal autophagy and oxidative stress contribute to angiotensin II- (Ang II-) induced cardiac hypertrophy and heart failure. We previously showed that Ang II increased Rap1GAP gene expression in cardiomyocytes associated with hypertrophy and autophagy disorders. Using real-time PCR and Western blot, we found that Rap1GAP expression was increased in the heart of Sprague Dawley (SD) rats infused by Ang II compared with saline infusion and in Ang II vs. vehicle-treated rat neonatal cardiomyocytes. Overexpression of Rap1GAP in cultured cardiomyocytes exacerbated Ang II-induced cardiomyocyte hypertrophy, reactive oxygen species (ROS) generation, and cell apoptosis and inhibited autophagy. The increased oxidative stress caused by Rap1GAP overexpression was inhibited by the treatment of autophagy agonists. Knockdown of Rap1GAP by siRNA markedly attenuated Ang II-induced cardiomyocyte hypertrophy and oxidative stress and enhanced autophagy. The AMPK/AKT/mTOR signaling pathway was inhibited by overexpression of Rap1GAP and activated by the knockdown of Rap1GAP. These results show that Rap1GAP-mediated pathway might be a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which could be a potential target for the future treatment of cardiac hypertrophy and heart failure.

Role of angiotensin-signalling in anthracycline-induced cardiotoxicity

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Findlay ◽  
J.H Gill ◽  
R Plummer ◽  
C.J Plummer
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Late Onset ◽  
Left Ventricular Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Funding Source ◽  
Study Results

Abstract   Anthracycline chemotherapy remains a key component of cancer treatment regimens in both paediatric and adult patients. A significant issue with their use is the development of anthracycline-induced cardiotoxicity (AIC), with subclinical AIC and clinical heart failure observed in 13.8% and 3.1% of patients, respectively. The major clinical complication of AIC is the development of late-onset cardiotoxicity, occurring several years after drug administration, presenting as life-threatening heart failure (HF). Determining the relationship between subclinical AIC and late-onset HF, strategies for mitigation of AIC, and impacts upon the cancer survivor population remains a complex challenge. Administration of drugs targeting the angiotensin system, specifically angiotensin converting enzyme inhibitors (ACEi), have been reported to reduce AIC in the clinic. Whilst the therapeutic effect of ACEi in management of left ventricular systolic dysfunction and consequent HF is principally through optimisation of cardiac haemodynamics, the mechanism involved with mitigation of late-onset AIC several years after anthracycline exposure are currently unknown. Using a variety of human cardiomyocyte in vitro models we have previously demonstrated induction of cardiomyocyte hypertrophy by angiotensin II and anthracyclines. Importantly, selective blockade of the angiotensin II receptor 1 (ATR1) on cardiomyocytes mitigated the anthracycline-induced hypertrophic response, implicating synergism between AIC and angiotensin signalling in cardiomyocytes. Adult human ventricular cardiac myocyte AC10 cell-line were treated in vitro with a range of clinically relevant doxorubicin doses for clinically appropriate durations, with AT1 receptor gene expression evaluated using semi-quantitative PCR. Our results confirm a positive correlation between clinically-relevant concentration of doxorubicin and induction of genetic expression of ATR1 in AC10 cells, with up to 200% increases in ATR1 expression observed. Maximal doxorubicin-induced gene expression being observed at 8 and 24-hours, respectively. These preliminary results agreeing with clinical exposure parameters for this drug with protein expression studies being optimised to support these gene expression study results. Our preliminary studies also imply patients developing AIC carry a deleted polymorphism within intron 16 of the ACE gene and increased systemic levels of the ACE product angiotensin II, both with a known association to hypertrophic cardiomyopathy. Taken together, these data support our mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes, involving structural cellular changes and asymptomatic cardiac hypertrophy. An elevation in angiotensin II levels, potentially through polymorphisms in ACE, could thereby exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced HF. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK funded PhD

scholarly journals Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

2016 ◽  
Vol 38 (5) ◽  
pp. 1743-1751 ◽  
Author(s):  
Haifeng Zhang ◽  
Shanshan Li ◽  
Qiulian Zhou ◽  
Qi Sun ◽  
Shutong Shen ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Immunofluorescent Staining ◽  
Mouse Heart ◽  
Mrna Levels ◽  
Elevated Protein ◽  
Ischemic Stress

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.

Differential Regulation of Ventricular Adrenomedullin and Atrial Natriuretic Peptide Gene Expression in Pressure and Volume Overload in the Rat

1998 ◽  
Vol 94 (4) ◽  
pp. 359-365 ◽  
Author(s):  
Michael Kaiser ◽  
Ole Kahr ◽  
Yasuyuki Shimada ◽  
Pamela Smith ◽  
Martin Kelly ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Atrial Natriuretic Peptide ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Mrna Level ◽  
Mrna Levels ◽  
Post Surgery ◽  
Infarction Heart ◽  
Atrial Natriuretic

1. Adrenomedullin is a recently discovered vasodilating and natriuretic peptide whose physiological and pathophysiological roles remain to be established. Like atrial natiuretic peptide adrenomedullin is expressed in the left ventricle. Ventricular expression of atrial natriuretic peptide is known to be markedly increased by volume or pressure overload. In this study we investigated whether ventricular expression of adrenomedullin is similarly stimulated under such conditions. 2. Ventricular adrenomedullin and atrial natriuretic peptide mRNA levels as well as those of a loading control mRNA (glyceraldehyde-3-phosphate dehydrogenase) were quantified by Northern blot analysis in (a) rats with severe post-infarction heart failure induced by left coronary ligation at 30 days post-surgery and (b) in rats with pressure-related cardiac hypertrophy induced by aortic banding at several time points (0.5, 1 and 4 h, and 1, 4, 7 and 28 days) after surgery. Levels were compared with those in matched sham-operated controls. 3. The mRNA level of atrial natriuretic peptide was markedly increased (8–10-fold) in the left ventricle of animals with post-infarction heart failure. In contrast, there was only a modest (40%) increase in the level of adrenomedullin mRNA. In rats with pressure-induced cardiac hypertrophy the ventricular level of atrial natriuretic peptide mRNA was again markedly increased (maximum 10-fold). The increase was first noticeable at 24 h post-banding and persisted until 28 days. In contrast, there was no change in adrenomedullin mRNA level compared with sham-operated rats at any time point. 4. Despite having similar systemic effects, the expression of adrenomedullin and atrial natriuretic peptide in the left ventricle is differently regulated. The findings imply distinct roles for the two peptides. The results do not support an important role for ventricular adrenomedullin expression in the remodelling process that occurs during the development of cardiac hypertrophy but suggest that ventricular adrenomedullin participates in the local and/or systemic response to heart failure

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

2018 ◽  
Vol 46 (05) ◽  
pp. 1021-1044 ◽  
Author(s):  
Simei Sun ◽  
Tianyi Li ◽  
Li Jin ◽  
Zhe Hao Piao ◽  
Bin Liu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Mapk Signaling ◽  
Cardiomyocyte Hypertrophy ◽  
Marker Genes ◽  
H9c2 Cell ◽  
Small Interfering Rnas ◽  
Dihydroxybenzoic Acid ◽  
Anticancer Activities ◽  
Dendropanax Morbifera

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.

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1304-1312
Author(s):  
Nurmila Sari ◽  
Yasufumi Katanasaka ◽  
Hiroki Honda ◽  
Yusuke Miyazaki ◽  
Yoichi Sunagawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Transcription ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

scholarly journals Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

2015 ◽  
Vol 36 (4) ◽  
pp. 1597-1612 ◽  
Author(s):  
Lei Liu ◽  
Chao Wang ◽  
Dianjun Sun ◽  
Shuangquan Jiang ◽  
Hong Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Intracellular Calcium Concentration ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Sham Operation ◽  
Ang Ii

Background/Aims: Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.

Sign in / Sign up

Export Citation Format

Share Document