Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

Cardiac hypertrophy is an important characteristic in the development of hypertensive heart disease. Mitochondrial dysfunction plays an important role in the pathology of cardiac hypertrophy. Recent studies have shown that sirtuin 3 (SIRT3)/poly (ADP-ribose) polymerase-1 (PARP-1) pathway modulation inhibits cardiac hypertrophy. Quercetin, a natural flavonol agent, has been reported to attenuate cardiac hypertrophy. However, the molecular mechanism is not completely elucidated. In this study, we aimed to explore the mechanism underlying the protective effect of quercetin on cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) were treated with quercetin (20 mg/kg/d) for 8 weeks to evaluate the effects of quercetin on blood pressure and cardiac hypertrophy. Additionally, the mitochondrial protective effect of quercetin was assessed in H9c2 cells treated with Ang II. SHRs displayed aggravated cardiac hypertrophy and fibrosis, which were attenuated by quercetin treatment. Quercetin also improved cardiac function, reduced mitochondrial superoxide and protected mitochondrial structure in vivo. In vitro, Ang II increased the mRNA level of hypertrophic markers including atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), whereas quercetin ameliorated this hypertrophic response. Moreover, quercetin prevented mitochondrial function against Ang II induction. Importantly, mitochondrial protection and PARP-1 inhibition by quercetin were partly abolished after SIRT3 knockdown. Our results suggested that quercetin protected mitochondrial function by modulating SIRT3/PARP-1 pathway, contributing to the inhibition of cardiac hypertrophy.

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LncRNA4930473A02Rik promotes cardiac hypertrophy by regulating TCF7 via sponging miR-135a in mice

Cell Death Discovery ◽

10.1038/s41420-021-00775-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jing Ren ◽

Hanping Qi ◽

Chao Song ◽

Lina Ba ◽

Renling Liu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Protective Effect ◽

Heart Function ◽

Luciferase Assay ◽

Mouse Heart ◽

Ang Ii ◽

Downstream Target ◽

Underlying Mechanisms

AbstractCardiac hypertrophy is a common pathological change accompanied by various cardiovascular diseases; however, its underlying mechanisms remain elusive. Mounting evidence indicates that long non-coding RNAs (lncRNAs) are novel transcripts involved in regulating multiple biological processes. However, little is known about their role in regulating cardiac hypertrophy. This study revealed a novel lncRNA4930473A02Rik (abbreviated as lncRNAA02Rik), which showed considerably increased expression in hypertrophic mouse hearts in vivo and angiotensin-II (Ang-II)-induced hypertrophic cardiomyocytes in vitro. Notably, lncRNAA02Rik knockdown partly ameliorated Ang-II induced hypertrophic cardiomyocytes in vitro and hypertrophic mouse heart function in vivo, whereas lncRNAA02Rik overexpression promoted cardiac hypertrophy in vitro. Furthermore, lncRNAA02Rik acted as a competing endogenous RNA by sponging miR-135a, while forced expression of lncRNAA02Rik could repress its activity and expression. Furthermore, forcing miR-135a overexpression exerted a significant protective effect against cardiac hypertrophy by inhibiting the activity of its downstream target TCF7, a critical member of Wnt signaling, and the protective effect could be reversed by AMO-135a. Luciferase assay showed direct interactions among lncRNAA02Rik, miR-135a, and TCF7. Altogether, our study demonstrated that lncRNAA02Rik upregulation could promote cardiac hypertrophy development via modulating miR-135a expression levels and TCF7 activity. Therefore, lncRNAA02Rik inhibition might be considered as a novel potential therapeutic strategy for cardiac hypertrophy.

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ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

Cell & Bioscience ◽

10.1186/s13578-021-00563-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tao Liang ◽

Weijian Hang ◽

Jiehui Chen ◽

Yue Wu ◽

Bin Wen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Calcium Transport ◽

Calcium Overload ◽

Mitochondrial Calcium ◽

Mitochondrial Impairment

Abstract Background Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

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A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice

Clinical Science ◽

10.1042/cs20180160 ◽

2018 ◽

Vol 132 (6) ◽

pp. 685-699 ◽

Cited By ~ 20

Author(s):

Zhen-Guo Ma ◽

Xin Zhang ◽

Yu-Pei Yuan ◽

Ya-Ge Jin ◽

Ning Li ◽

...

Keyword(s):

T Cell ◽

Cardiac Hypertrophy ◽

Protective Effect ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Akt Signaling ◽

Akt Signaling Pathway

T-cell infiltration and the subsequent increased intracardial chronic inflammation play crucial roles in the development of cardiac hypertrophy and heart failure (HF). A77 1726, the active metabolite of leflunomide, has been reported to have powerful anti-inflammatory and T cell-inhibiting properties. However, the effect of A77 1726 on cardiac hypertrophy remains completely unknown. Herein, we found that A77 1726 treatment attenuated pressure overload or angiotensin II (Ang II)-induced cardiac hypertrophy in vivo, as well as agonist-induced hypertrophic response of cardiomyocytes in vitro. In addition, we showed that A77 1726 administration prevented induction of cardiac fibrosis by inhibiting cardiac fibroblast (CF) transformation into myofibroblast. Surprisingly, we found that the protective effect of A77 1726 was not dependent on its T lymphocyte-inhibiting property. A77 1726 suppressed the activation of protein kinase B (AKT) signaling pathway, and overexpression of constitutively active AKT completely abolished A77 1726-mediated cardioprotective effects in vivo and in vitro. Pretreatment with siRNA targetting Fyn (si Fyn) blunted the protective effect elicited by A77 1726 in vitro. More importantly, A77 1726 was capable of blocking pre-established cardiac hypertrophy in mice. In conclusion, A77 1726 attenuated cardiac hypertrophy and cardiac fibrosis via inhibiting FYN/AKT signaling pathway.

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β-catenin/LEF1/IGF-IIR Signaling Axis Galvanizes the Angiotensin-II- induced Cardiac Hypertrophy

International Journal of Molecular Sciences ◽

10.3390/ijms20174288 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4288 ◽

Cited By ~ 5

Author(s):

Chin-Hu Lai ◽

Sudhir Pandey ◽

Cecilia Hsuan Day ◽

Tsung-Jung Ho ◽

Ray-Jade Chen ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Tissue ◽

Ang Ii ◽

Consensus Binding Site ◽

Tissue Samples ◽

Spontaneously Hypertensive ◽

Signaling Axis ◽

Causes Of Mortality

Cardiovascular diseases have a high prevalence worldwide and constitute the leading causes of mortality. Recently, malfunctioning of β-catenin signaling has been addressed in hypertensive heart condition. Ang-II is an important mediator of cardiovascular remodeling processes which not only regulates blood pressure but also leads to pathological cardiac changes. However, the contribution of Ang-II/β-catenin axis in hypertrophied hearts is ill-defined. Employing in vitro H9c2 cells and in vivo spontaneously hypertensive rats (SHR) cardiac tissue samples, western blot analysis, luciferase assays, nuclear-cytosolic protein extracts, and immunoprecipitation assays, we found that under hypertensive condition β-catenin gets abnormally induced that co-activated LEF1 and lead to cardiac hypertrophy changes by up-regulating the IGF-IIR signaling pathway. We identified putative LEF1 consensus binding site on IGF-IIR promoter that could be regulated by β-catenin/LEF1 which in turn modulate the expression of cardiac hypertrophy agents. This study suggested that suppression of β-catenin expression under hypertensive condition could be exploited as a clinical strategy for cardiac pathological remodeling processes.

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MiR-195-5p Promotes Cardiomyocyte Hypertrophy by Targeting MFN2 and FBXW7

BioMed Research International ◽

10.1155/2019/1580982 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Lei Wang ◽

Dongze Qin ◽

Hongtao Shi ◽

Yanan Zhang ◽

Hao Li ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Target Genes ◽

Statistical Significance ◽

Luciferase Reporter ◽

Cardiomyocyte Hypertrophy ◽

Ang Ii ◽

Mrna Targets ◽

H9c2 Cardiomyocytes

Cardiac hypertrophy mainly predicts heart failure and is highly linked with sudden loss of lives. MicroRNAs (miRNAs) play essential roles in the development of cardiac hypertrophy through binding to corresponding mRNA targets. In this study, in order to investigate the roles of two mature forms of miRNA-195, miR-195-3p, and miR-195-5p, in vitro and in vivo models of cardiac hypertrophy were established by applying angiotensin II (Ang II) to H9c2 cardiomyocytes and infusing chronic Ang II to mice, respectively. We found that miR-195-5p was evidently equally upregulated in the in vitro and in vivo studies of cardiac hypertrophy induced by Ang II. High expressed miR-195-5p could adequately promote hypertrophy, whereas the suppression of miR-195-5p prevented hypertrophy of H9c2 cardiomyocytes under Ang II treatment. Furthermore, the luciferase reporter system demonstrated that MFN2 and FBWX7 were target genes of miR-195-5p, which negatively regulated the expression of these two genes in H9c2 cells. By contrast, in both models, expression of miR-195-3p was only slightly changed without statistical significance. In addition, we observed a trend towards decreased expression of hypertrophic markers by overexpressing miR-195-3p in AngII-treated H9c2 cardiomyocytes in vitro. Taken together, our study indicates that miR-195-5p promotes cardiac hypertrophy via targeting MFN2 and FBXW7 and may provide promising therapeutic strategies for interfering cardiac hypertrophy.

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(–)-Epicatechin Suppresses Angiotensin II-induced Cardiac Hypertrophy via the Activation of the SP1/SIRT1 Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000475396 ◽

2017 ◽

Vol 41 (5) ◽

pp. 2004-2015 ◽

Cited By ~ 14

Author(s):

Zeng-xiang Dong ◽

Lin Wan ◽

Ren-jun Wang ◽

Yuan-qi Shi ◽

Guang-zhong Liu ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Cardiomyocyte Hypertrophy ◽

Ang Ii ◽

Beneficial Effects ◽

Protein Levels ◽

Qrt Pcr

Background/Aims: Flavonol (–)-epicatechin (EPI) is present in high amounts in cocoa and tea products, and has been shown to exert beneficial effects on the cardiovascular system. However, the precise mechanism of EPI on cardiomyocyte hypertrophy has not yet been determined. In this study, we examined whether EPI could inhibit cardiac hypertrophy. Methods: We utilised cultured neonatal mouse cardiomyocytes and mice for immunofluorescence, immunochemistry, qRT-PCR, and western blot analyses. Results: 1µM EPI significantly inhibited 1µM angiotensin II (Ang II)-induced increase of cardiomyocyte size, as well as the mRNA and protein levels of ANP, BNP and β-MHC in vitro. The effects of EPI were accompanied with an up-regulation of SP1 and SIRT1, and were abolished by SP1 inhibition. Up-regulation of SP1 could block Ang II-induced increase in cardiomyocyte size, as well as the mRNA and protein levels of ANP, BNP and β-MHC, and increase the protein levels of SIRT1 in vitro. Moreover, 1 mg/kg body weight/day EPI significantly inhibited mouse cardiac hypertrophy induced by Ang II, which could be eliminated by SP1 inhibition in vivo. Conclusion: Our data indicated that EPI inhibited AngII-induced cardiac hypertrophy by activating the SP1/SIRT1 signaling pathway.

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Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling

Pharmacology ◽

10.1159/000518464 ◽

2021 ◽

pp. 1-15

Author(s):

Yong Chen ◽

Ting He ◽

Zhongjun Zhang ◽

Junzhi Zhang

Keyword(s):

Cardiac Hypertrophy ◽

Protective Effect ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Left Ventricular ◽

Neonatal Rat ◽

Ang Ii ◽

Tgf Β1

Introduction: Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms. Methods: In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-β1 (TGF-β1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques. Results: In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-β1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-β1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-β1/p-Smad3 expression. Conclusions: Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-β1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.

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Hispidulin Attenuates Cardiac Hypertrophy by Improving Mitochondrial Dysfunction

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.582890 ◽

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.

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Knockdown of TUG1 rescues cardiomyocyte hypertrophy through targeting the miR-497/MEF2C axis

Open Life Sciences ◽

10.1515/biol-2021-0025 ◽

2021 ◽

Vol 16 (1) ◽

pp. 242-251

Author(s):

Guorong Zhang ◽

Xinghua Ni

Keyword(s):

Cardiac Hypertrophy ◽

Noncoding Rna ◽

Protective Role ◽

Luciferase Reporter ◽

Cardiomyocyte Hypertrophy ◽

Ang Ii ◽

Western Blot Assay ◽

Rna Immunoprecipitation

Abstract The aim of this study was to investigate the detailed role and molecular mechanism of long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) in cardiac hypertrophy. Cardiac hypertrophy was established by transverse abdominal aortic constriction (TAC) in vivo or angiotensin II (Ang II) treatment in vitro. Levels of lncRNA TUG1, miR-497 and myocyte enhancer factor 2C (MEF2C) mRNA were assessed by quantitative reverse transcriptase PCR (qRT-PCR). Western blot assay was performed to determine the expression of MEF2C protein. The endogenous interactions among TUG1, miR-497 and MEF2C were confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. Our data indicated that TUG1 was upregulated and miR-497 was downregulated in the TAC rat model and Ang II-induced cardiomyocytes. TUG1 knockdown or miR-497 overexpression alleviated the hypertrophy induced by Ang II in cardiomyocytes. Moreover, TUG1 acted as a sponge of miR-497, and MEF2C was directly targeted and repressed by miR-497. miR-497 overexpression mediated the protective role of TUG1 knockdown in Ang II-induced cardiomyocyte hypertrophy. MEF2C was a functional target of miR-497 in regulating Ang II-induced cardiomyocyte hypertrophy. In addition, TUG1 regulated MEF2C expression through sponging miR-497. Knockdown of TUG1 rescued Ang II-induced hypertrophy in cardiomyocytes at least partly through targeting the miR-497/MEF2C axis, highlighting a novel promising therapeutic target for cardiac hypertrophy treatment.

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STING protects against cardiac dysfunction and remodelling by blocking autophagy

10.21203/rs.3.rs-154343/v2 ◽

2021 ◽

Author(s):

Rui Xiong ◽

Ning Li ◽

Wei Wang ◽

Bo Wang ◽

Wenyang Jiang ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Protein Expression ◽

Cardiac Fibroblasts ◽

Cardiac Remodelling ◽

Ang Ii ◽

Mrna And Protein Expression

Abstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway. Results In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757. Conclusions STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure.

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