Smad7 inhibits angiotensin II-induced hypertensive cardiac remodelling

Wei, Lihua; Huang, Xiao‐Ru; Zhang, Yang; Li, Youqi; Chen, Haiyong; Yan, Bryan P.; Yu, Cheuk‐Man; Lan, Hui‐Yao

doi:10.1093/cvr/cvt151

Cited by 60 publications

(88 citation statements)

References 37 publications

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“…23,24 Given that Smad7 interferes with Smad2/3 activation, cardiac Smad7 overexpression blocked TGF-b1 signaling. 25 Our results indicated a significant increase in TGF-b1 expression and Smad2/3 phosphorylation, as well as decreased Smad7. AA treatment blocked Smad2/3 activation and increased Smad7 expression.…”

Section: Discussionsupporting

confidence: 52%

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice

et al. 2015

Journal of Cardiovascular Pharmacology

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Cardiac structural remodeling, including cardiomyocyte apoptosis, interstitial fibrosis, and inflammation, appears to be a key event associated with the progression of left ventricular hypertrophy and heart failure. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica that exhibits antiapoptotic, antifibrotic, and anti-inflammatory activities. In the present study, a transverse aortic constriction (TAC) model was created in mice to mimic the progression of hypertrophy (2 weeks post-TAC) and heart failure (4 weeks post-TAC) to investigate whether the potential therapeutic drug AA ameliorates hypertrophy progression and which mechanisms are involved in this amelioration. Our results demonstrated that AA markedly inhibited the process of progression induced by pressure overload. The increases cardiomyocyte apoptosis and interstitial fibrosis, and inflammatory responses were significantly suppressed by AA. Our investigation revealed that this inhibitory effect was mediated by blocking the activation of both mitochondrial and death receptor-dependent apoptotic signaling pathways. Additional experiments demonstrated that AA attenuated fibrosis by blocking both transforming growth factor-β1/Smad and interleukin-6, signaling activation. Consequently, these findings indicated that AA attenuated pathological cardiac structural remodeling and preserved cardiac function via multiple intracellular signaling pathways in response to cardiac stimuli.

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Section: Discussionsupporting

confidence: 52%

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice

et al. 2015

Journal of Cardiovascular Pharmacology

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“…Smad7 is an important inhibitory Smad that suppresses Smad2/3 activation and reduces the fibrotic response [19,20,21,22]. Our results suggest that upregulation of Smad7 may be a key to ameliorating atrial fibrosis with EPL.…”

Section: Resultsmentioning

confidence: 78%

“…Third, knockdown of Smad7 abolished the protective roles of EPL. Consistently, Smad7, a downstream inhibitory Smad in TGF-β 1 signaling, was demonstrated to block phosphorylation and activation of Smad2/3 [21,27,28]. Overexpression of Smad7 inhibited collagen synthesis in cardiac myofibroblasts of adult rats [29].…”

Section: Discussionmentioning

confidence: 97%

Eplerenone Prevents Atrial Fibrosis via the TGF-β Signaling Pathway

Qin²,

Yi³

et al. 2017

Cardiology

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Objectives: Eplerenone (EPL), an antagonist of the mineralocorticoid receptor, is beneficial for atrial fibrillation and atrial fibrosis. However, the underlying mechanism remains less well known. We aimed to investigate the effect of EPL on atrial fibrosis using a mouse with selective atrial fibrosis and to explore the underlying mechanisms. Methods: EPL-treated MHC-TGFcys³³ser transgenic mice that have selective atrial fibrosis (Tx+EPL mice), as well as control mice, were used for in vivo studies including histological analyses, Western blotting, and qRT-PCR studies. TGF-β₁-stimulated atrial fibroblasts were treated with EPL or vehicle for the in vitro studies including Western blotting and qRT-PCR studies. In addition, Smad7 siRNA was used to knock down Smad7. Results: EPL inhibited atrial fibrosis in the Tx mice. In addition, EPL suppressed the expression of fibrosis-related molecules induced by TGF-β₁ in vivo and in vitro. This occurred in concert with a downregulation of Smad7 protein expression and an upregulation of p-Smad2/3 protein expression. In addition, knockdown of Smad7 by siRNA abolished the protective roles of EPL. Conclusions: EPL inhibited atrial fibrosis in Tx mice. The underlying mechanism may involve increased protein expression of Smad7, which enhances the inhibitory feedback regulation of TGF-β₁/Smad signaling.

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“…With inhibition of the renin-angiotensin system, clinical trials demonstrated significant benefit in the prevention of cardiac remodeling and myocardial fibrosis [19,20]. Moreover, Ang II given exogenously to rodents has been shown to result in cellular changes within the myocardium, hypertrophy and eventual fibrosis, similar to that seen in humans [20,21,22,23]. Taken together, this evidence strongly supports a role for Ang II in the development of myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 86%

Downregulation of MicroRNA-19b Contributes to Angiotensin II-Induced Overexpression of Connective Tissue Growth Factor in Cardiomyocytes

Gao¹,

Liu

Wang

et al. 2013

Cardiology

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Objectives: The present study was designed to decipher the molecular mechanisms underlying angiotensin (Ang) II-induced overexpression of connective tissue growth factor (CTGF) in cultured cardiomyocytes. Methods: Cardiomyocytes isolated from 1- to 3-day-old neonatal rats were cultured and treated with 100 nM Ang II with or without pretreatment with 10 nM telmisartan, an Ang II type 1 receptor antagonist. The role of microRNA (miR)-19b in the regulation of Ang II-induced CTGF expression was evaluated in cultured cardiomyocytes with quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. Results: We provide several lines of evidence to show that miR-19b contributes to the Ang II-induced overexpression of CTGF in cultured cardiomyocytes. Firstly, administration of Ang II decreased the level of miR-19b dramatically (p < 0.05 vs. control), which was abolished by telmisartan. Secondly, Ang II increased the level of CTGF significantly (p < 0.05 vs. control), which was also prevented by pretreatment with telmisartan. Thirdly, overexpression of miR-19b decreased CTGF levels (p < 0.05 vs. control). Finally, transfection of miR-19b into cardiomyocytes prevented the upregulation of CTGF induced by Ang II. Conclusion: Downregulation of miR-19b contributes to Ang II-induced overexpression of CTGF in cultured cardiomyocytes.

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Smad7 inhibits angiotensin II-induced hypertensive cardiac remodelling

Abstract: Smad7 plays a protective role in Ang II-induced cardiac remodelling via mechanisms involving the Sp1-TGF-β/Smad-NF-κB-miR-29 regulatory network. Thus, Smad7 may be a novel therapeutic agent for hypertensive cardiovascular diseases.

Cited by 60 publications

References 37 publications

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice

Eplerenone Prevents Atrial Fibrosis via the TGF-β Signaling Pathway

Downregulation of MicroRNA-19b Contributes to Angiotensin II-Induced Overexpression of Connective Tissue Growth Factor in Cardiomyocytes

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