Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein*

Kuno, Atsushi; Hori, Yusuke S.; Hosoda, Ryusuke; Tanno, Masaya; Miura, Tetsuji; Shimamoto, Kazuaki; Horio, Yoshiyuki

doi:10.1074/jbc.m112.392050

Cited by 79 publications

(86 citation statements)

References 30 publications

(20 reference statements)

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“…31,32 Moreover, the administration of RSV, a specific SIRT1 activator, suppressed cardiac hypertrophy and restored cardiac function, suggesting that SIRT1 is essential for cardiomyocyte development. 33,34 Previous studies showed that JNK activation influences SIRT1 protein stability, 24,25 consistent with our observations. We found that a JNK1/2 activator (anisomycin) promoted SIRT1 degradation via the ubiquitinproteasome system.…”

Section: Discussionsupporting

confidence: 82%

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

Huang

et al. 2014

Cell Death Differ

115

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Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt À 748 to À 585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF-IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients. Apoptosis has been implicated in a wide variety of cardiovascular disorders, including myocardial infarction and heart failure, suggesting that activation of apoptotic pathways contributes to cardiomyocyte loss and subsequently cardiac dysfunction. Previous studies reported that several extracellular molecules, such as insulin-like growth factors (IGFs) and angiotensin II (ANG II), are involved in the development of cardiac hypertrophy and apoptosis.

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Section: Discussionsupporting

confidence: 82%

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

Huang

et al. 2014

Cell Death Differ

115

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“…Studies have shown that NO donation 45,46 or antioxidant therapy 47,48 has beneficial effects in the mdx mouse models. For example, restoration of the NO-cGMP pathway 3,49,50 with phosphodiesterase-5 inhibitors, such as sildenafil, improved cardiac pathology in mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy

Afzal

Reiter

Gastonguay

et al. 2016

J Cardiovasc Pharmacol Ther

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“…RSV administration exerts beneficial effects against cardiovascular and neurodegenerative diseases [4]. We previously showed that RSV retards the progression of chronic heart failure in cardiomyopathic TO2 hamsters [13] and suppresses the skeletal and cardiac muscle pathologies in dystrophin-deficient mdx mice, a model of Duchenne muscular dystrophy [14], [15]. Such beneficial effects are thought to be at least partly attributable to the increased SIRT1 activity [11], [13]–[15].…”

Section: Introductionmentioning

confidence: 99%

Regulation of FOXOs and p53 by SIRT1 Modulators under Oxidative Stress

et al. 2013

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Excessive reactive oxygen species (ROS) induce apoptosis and are associated with various diseases and with aging. SIRT1 (sirtuin-1), an NAD+-dependent protein deacetylase, decreases ROS levels and participates in cell survival under oxidative stress conditions. SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death. In this study, we aimed to know which is working greatly among p53 and FOXOs transcription factors in SIRT1’s cell protective functions under oxidative stress conditions. The antimycin A-induced increase in ROS levels and apoptosis was enhanced by SIRT1 inhibitors nicotinamide and splitomicin, whereas it was suppressed by a SIRT1 activator, resveratrol, and a SIRT1 cofactor, NAD+. SIRT1-siRNA abolished the effects of splitomicin and resveratrol. p53-knockdown experiment in C2C12 cells and experiment using p53-deficient HCT116 cells showed that splitomicin and resveratrol modulated apoptosis by p53-dependent and p53-independent pathways. In p53-independent cell protective pathway, we found that FOXO1, FOXO3a, and FOXO4 were involved in SOD2’s upregulation by resveratrol. The knockdown of these three FOXOs by siRNAs completely abolished the SOD2 induction, ROS reduction, and anti-apoptotic function of resveratrol. Our results indicate that FOXO1, FOXO3a and FOXO4, are indispensable for SIRT1-dependent cell survival against oxidative stress, although deacetylation of p53 has also some role for cell protective function of SIRT1.

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Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein*

Cited by 79 publications

References 30 publications

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation

Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy

Regulation of FOXOs and p53 by SIRT1 Modulators under Oxidative Stress

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