Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

2006 ◽  
Vol 26 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Xin Tian ◽  
Jusan Yang ◽  
Shannon M. Dunlay ◽  
Andrew S. Peek ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Dominant Negative ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Signaling Cascade ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

P5395Exercise-induced miR-17-3p Prevents Pathological Myocardial Dysfunction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Q Zhou ◽  
J Xiao
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Area ◽  
Ang Ii ◽  
Upstream Regulator ◽  
Exercise Induced

Abstract Background Exercise is beneficial for pathological myocardial dysfunction and heart failure. We previously reported that miR-17-3p contributed to exercise-induced cardiac growth and protected against cardiac ischemia/reperfusion injury. However, if exercise-induced miR-17-3p can prevent pathological myocardial dysfunction is undetermined. Purpose To investigate if exercise-induced miR-17-3p can prevent pathological myocardial dysfunction. Methods The miR-17-3p expression was examined in phenylephrine (PE, 50μmol/L, 48 h) and angiotensin II (Ang II, 1μmol/L, 48 h) treated primary neonatal rat ventricular cardiomyocytes (NRCM), and the myocardium of thoracic aortic constriction (TAC, 4weeks) or angiotensin II (1.3 mg/kg/day, 4weeks) induced cardiac hypertrophy murine model. miR-17-3p transgenic mice were generated and subjected to TAC or Ang II to investigate the effect of miR-17-3p overexpression in attenuating pathological cardiac dysfunction by echocardiography. Cell area and hypertrophic genes were determined by Wheat Germ Agglutinin (WGA) staining and qRT-PCRs. In addition, cell area and hypertrophic genes (ANP, BNP, β-MHC) were determined by immunolabeling and qRT-PCR in NRCM after the transfection of miR-17-3p mimic or inhibitor. Furthermore, functional rescue assays were performed to identify phosphatase and tensin homolog (PTEN) as a target gene of miR-17-3p, and myocyte enhancer factor 2C (MEF2C) as an upstream regulator of miR-17-3p in pathological cardiac hypertrophy. Results The expression of miR-17-3p was significantly decreased in the heart from TAC or Ang II mouse model, and in PE or Ang II-induced cardiomyocyte hypertrophy model. miR-17-3p overexpression mice displayed improved cardiac function and reduced cardiac hypertrophy after TAC or Ang II treatment in vivo. miR-17-3p mimic significantly attenuated PE or Ang II-induced cardiomyocyte hypertrophy in vitro. Based on functional rescue experiments, PTEN was identified as a direct target of miR-17-3p that mediated its protective effects in cardiac hypertrophy. Moreover, MEF2C was identified as a negative upstream regulator of miR-17-3p involved in the control of cardiac hypertrophy. Proposed mechanism of miR-17-3p Conclusion Exercise-induced miR-17-3p can prevent pathological myocardial dysfunction by targeting PTEN. MEF2C was an upstream regulator of miR-17-3p. Targeting MEF2C/miR-17-3p/ PTEN represents a novel therapeutic strategy for pathological myocardial dysfunction. Acknowledgement/Funding The grants from National Natural Science Foundation of China (81722008, 91639101 and 81570362 to JJ Xiao)

scholarly journals Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro

2000 ◽  
Vol 347 (1) ◽  
pp. 275-284 ◽  
Author(s):  
Hiroki AOKI ◽  
Mary RICHMOND ◽  
Seigo IZUMO ◽  
Junichi SADOSHIMA
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Specific Inhibitor ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Specific Response ◽  
Erk Pathway ◽  
Ang Ii ◽  
Extracellular Signal

Although MAP (mitogen-activated protein) kinases are implicated in cell proliferation and differentiation in many cell types, the role of MAP kinases in cardiac hypertrophy remains unclear. We examined the role of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAP kinase in angiotensin II (Ang II)-induced hypertrophy compared with phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. Both Ang II and phenylephrine activated ERKs to a similar extent, whereas phenylephrine caused stronger and more sustained activation of JNK and p38 than Ang II. PD98059, a specific inhibitor of MAPK/ERK kinase (MEK),inhibited Ang II-induced, but not phenylephrine-induced, expression of atrial natriuretic factor (ANF) at both the mRNA and polypeptide levels. SB203580, a specific inhibitor of p38 and some JNK isoforms, did not show significant effects on ANF expression induced by Ang II or phenylephrine. Although PD98059 and dominant-negative MEK1 blocked Ang II-induced activation of the ANF promoter, SB203580 or dominant-negative MEK kinase 1 (MEKK1) showed no effect. Phenylephrine-induced ANF promoter activation was significantly inhibited by SB203580 and dominant-negative MEKK1, but not by PD98059 or dominant-negative MEK1. Dominant-negative Ras inhibited both ERK activation and ANF up-regulation by Ang II, whereas constitutively active forms of Ras and MEK were sufficient to activate the ANF promoter. Dominant-negative Ras also partly inhibited the phenylephrine-induced activation of ANF promoter. PD98059 did not affect other markers of Ang II-induced hypertrophy, such as skeletal α-actin and c-fos expression, increases in the rate of protein synthesis or rapid sarcomeric actin organization. These results suggest that Ang II uses ERK for ANF expression, whereas phenylephrine uses other pathways. The Ras/ERK pathway selectively mediates ANF expression in various phenotypes observed in Ang II-induced hypertrophy. The ERK pathway mediates an agonist-specific and phenotype-specific response in cardiac hypertrophy.

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

2017 ◽  
Vol 41 (5) ◽  
pp. 2004-2015 ◽  
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.

Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway

2019 ◽  
Vol 116 (1) ◽  
pp. 114-126 ◽  
Author(s):  
Xiaoying Yan ◽  
Ran Zhao ◽  
Xiaorong Feng ◽  
Jingzhou Mu ◽  
Ying Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Transforming Growth Factor ◽  
Troponin T ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii

Abstract Aims Sialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy. Methods and results Siat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt −1285 to −1274 bp) in the cardiomyocytes following ANG II stimulus. Conclusion Siat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.

scholarly journals Superoxide scavenging and Akt inhibition in myocardium ameliorate pressure overload-induced NF-κB activation and cardiac hypertrophy

2010 ◽  
Vol 41 (2) ◽  
pp. 127-136 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Zhenbo Li ◽  
William Kutschke ◽  
Xin Tian ◽  
Ram V. Sharma ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Viral Vectors ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Cardiomyocyte Hypertrophy ◽  
Luciferase Expression ◽  
Akt Activation ◽  
Dominant Negative Form

Recent studies from our laboratory and others have shown that increases in cytoplasmic superoxide (O2·−) levels and Akt activation play a key role in agonist-stimulated NF-κB activation and cardiomyocyte hypertrophy in vitro. In this study, we tested the hypothesis that adenovirus (Ad)-mediated intramyocardial gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD) or a dominant-negative form of Akt (AdDNAkt) in mice would attenuate pressure overload-induced increases in activation of the redox-sensitive transcription factor NF-κB and cardiac hypertrophy. Adult C57BL/6 mice were subjected to thoracic aortic banding (TAB) or sham surgery, and intramyocardial injections of viral vectors (AdCu/ZnSOD, AdDNAkt, or control) were performed. There was robust transgene expression in the heart, which peaked 6–7 days after injection and then declined to undetectable levels by 12–14 days. In mice injected with AdBgL II, TAB caused a significant increase in O2·− generation and cardiac mass at 1 wk, and these responses were markedly attenuated by AdCu/ZnSOD. In addition, TAB induced time-dependent activation of NF-κB in the myocardium as measured longitudinally by in vivo bioluminescent imaging of NF-κB-dependent luciferase expression. This was also abolished by intracardiac AdCu/ZnSOD or AdDNAkt, but not the control vector. The inhibition of Akt and O2·−-mediated NF-κB activation in TAB hearts was associated with an attenuation of cardiac hypertrophy. Since a direct cause-and-effect relationship between NF-κB activation and cardiomyocyte hypertrophy has been established previously, our data support the hypothesis that increased O2·− generation and Akt activation are key signaling intermediates in pressure overload-induced activation of NF-κB and cardiac hypertrophy.

Involvement of oxidants and AP-1 in angiotensin II-activated NFAT3 transcription factor

2007 ◽  
Vol 292 (4) ◽  
pp. C1248-C1255 ◽  
Author(s):  
Victoria C. Tu ◽  
Haipeng Sun ◽  
G. Tim Bowden ◽  
Qin M. Chen
Keyword(s):  
Transcription Factor ◽  
Angiotensin Ii ◽  
Binding Site ◽  
Dominant Negative ◽  
Cardiomyocyte Hypertrophy ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Activated T Cells ◽  
The Core ◽  
Phosphoinositide 3 Kinase

Cardiomyocyte hypertrophy is associated with multiple pathophysiological cardiovascular conditions. Recent studies have substantiated the finding that oxidants may contribute to the development of cardiomyocyte hypertrophy. Activation of the nuclear factor of activated T cells-3 (NFAT3) transcription factor has been shown to result from endocrine inducers of cardiomyocyte hypertrophy such as angiotensin II (ANG II) and serves as an important molecular regulator of cardiomyocyte hypertrophy. In this study, we found that antioxidant enzyme catalase and antioxidants N-acetyl-l-cysteine, α-phenyl- N- tert-butylnitrone, and lipoic acid prevent ANG II from activating NFAT3 promoter-luciferase. H2O2 induces a time- and dose-dependent activation of NFAT3 transcription factor. A dominant negative form of NFAT3 transcription factor inhibited H2O2 from activating NFAT3 promoter. An inhibitor of ERKs, but not phosphoinositide 3-kinase or p38 MAPKs, blocked NFAT3 activation by H2O2. The NFAT3 binding site in the promoters of most genes contains a weak activator protein-1 (AP-1) binding site adjacent to the core consensus NFAT binding sequence. ERK inhibitor PD98059 was found previously to inhibit AP-1 activation by H2O2. Inactivation of AP-1 transcription factor by cotransfection of a dominant negative c-Jun, TAM67, prevented H2O2 or ANG II from activating NFAT3 promoter. NFAT3 promoter containing the core NFAT cis-element without AP-1 binding site failed to show activation by H2O2 treatment. Our data suggest that hypertrophy inducers ANG II and H2O2 may activate NFAT3 in cardiomyocyte through an AP-1 transcription factor-dependent mechanism.

scholarly journals Kaempferol Alleviates Angiotensin II-Induced Cardiac Dysfunction and Interstitial Fibrosis in Mice

2017 ◽  
Vol 43 (6) ◽  
pp. 2253-2263 ◽  
Author(s):  
Yuan Liu ◽  
Lu Gao ◽  
Sen Guo ◽  
Yuzhou Liu ◽  
Xiaoyan Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiac Remodelling ◽  
Ang Ii ◽  
Ventricular Fibrosis

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) is a mechanism that promotes cardiac fibrosis induced by Angiotensin II (AngII). Kaempferol (KAE) is a monomer component mainly derived from the rhizome of Kaempferia galanga L. It shows anti-inflammatory, anti-oxidative, anti-microbial and anti-cancer properties, which can be used in the treatment of cancer, cardiovascular diseases, infection, etc. But, its effects on the development of cardiac remodelling remain completely unknown. The aim of the present study was to determine whether KAE attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and cardiac hypertrophy induced by AngII infusion in mice in vivo. Methods: Male wild-type mice aged 8-10 weeks with or without KAE were subjected to AngII or saline, to induce fibrosis or as a control, respectively. Morphological changes, echocardiographic parameters, histological analyses, and hypertrophic markers were also used to evaluate hypertrophy. Results: KAE prevented and reversed cardiac remodelling induced by AngII. The KAE in this model exerted no basal effects but attenuated cardiac fibrosis, hypertrophy and dysfunction induced by AngII. Both in vivo and in vitro experiments demonstrated that Ang II infusion or TGF-β induced EndMT can be reduced by KAE and the proliferation and activation of cardiac fibroblasts (CFs) can be inhibited by KAE. Conclusions: The results suggest that KAE prevents and reverses ventricular fibrosis and cardiac dysfunction, providing an experimental basis for clinical treatment on ventricular fibrosis.

scholarly journals MiR-27a-3p/Hoxa10 Axis Regulates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Targeting Kv4.3 Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuefeng Cao ◽  
Zheng Zhang ◽  
Yu Wang ◽  
Weichao Shan ◽  
Ruiting Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Pathological Process ◽  
Luciferase Assay ◽  
Cardiomyocyte Hypertrophy ◽  
Electrical Remodeling ◽  
Transcriptional Level ◽  
Ang Ii ◽  
Clinical Prevention

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases, which is often accompanied with structural and electrical remodeling, and can even lead to sudden cardiac death. However, its molecular mechanism still remains largely unknown. Here, we induced cardiomyocyte hypertrophy by angiotensin II (Ang II), and found that miR-27a-3p and hypertrophy-related genes were up-regulated. Further studies showed that miR-27a-3p-inhibitor can alleviate myocardial hypertrophy and electrical remodeling. Moreover, luciferase assay confirmed that miR-27a-3p could regulate the expression of downstream Hoxa10 at the transcriptional level by targeting at its 3′UTR. At the same time, the protein expression of Hoxa10 was significantly reduced in Ang II-treated cardiomyocytes. Furthermore, overexpression of Hoxa10 can reverse myocardial hypertrophy and electrical remodeling induced by Ang II in cardiomyocytes. Finally, we found that Hoxa10 positively regulated the expression of potassium channel protein Kv4.3 which was down-regulated in hypertrophic cardiomyocytes. Taken together, our results revealed miR-27a-3p/Hoxa10/Kv4.3 axis as a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which provided a new target for clinical prevention and treatment of cardiac hypertrophy and heart failure.

scholarly journals Lysosomal-Associated Protein Transmembrane 5 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

2021 ◽  
Vol 8 ◽  
Author(s):  
Lu Gao ◽  
Sen Guo ◽  
Rui Long ◽  
Lili Xiao ◽  
Rui Yao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Therapeutic Potential ◽  
Negative Regulator ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy

Lysosomal-associated protein transmembrane 5 (LAPTM5) is mainly expressed in immune cells and has been reported to regulate inflammation, apoptosis and autophagy. Although LAPTM5 is expressed in the heart, whether LAPTM5 plays a role in regulating cardiac function remains unknown. Here, we show that the expression of LAPTM5 is dramatically decreased in murine hypertrophic hearts and isolated hypertrophic cardiomyocytes. In this study, we investigated the role of LAPTM5 in pathological cardiac hypertrophy and its possible mechanism. Our results show that LAPTM5 gene deletion significantly exacerbates cardiac remodeling, which can be demonstrated by reduced myocardial hypertrophy, fibrosis, ventricular dilation and preserved ejection function, whereas the opposite phenotype was observed in LAPTM5 overexpression mice. In line with the in vivo results, knockdown of LAPTM5 exaggerated angiotensin II-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes, whereas overexpression of LAPTM5 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, LAPTM5 directly bound to Rac1 and further inhibited MEK-ERK1/2 signaling, which ultimately regulated the development of cardiac hypertrophy. In addition, the antihypertrophic effect of LAPTM5 was largely blocked by constitutively active mutant Rac1 (G12V). In conclusion, our results suggest that LAPTM5 is involved in pathological cardiac hypertrophy and that targeting LAPTM5 has great therapeutic potential in the treatment of pathological cardiac hypertrophy.

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.

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