Dataset Information

Sirtuin 1 represses PKC-? activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy.

ABSTRACT: BACKGROUND AND PURPOSE:Activation of PKC-? is closely linked to the pathogenesis of cardiac hypertrophy. PKC-? can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-? signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. EXPERIMENTAL APPROACH:Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-? was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo. KEY RESULTS:Overexpression of PKC-? led to cardiac hypertrophy and increased activity of NF-?B, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-?, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-? phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-?' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy. CONCLUSIONS AND IMPLICATIONS:Sirtuin1 is an endogenous negative regulator for PKC-? and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-? signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.

SUBMITTER: Li J

PROVIDER: S-EPMC6329629 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sirtuin 1 represses PKC-ζ activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy.

Li Jingyan J Huang Junying J Lu Jing J Guo Zhen Z Li Zhuoming Z Gao Hui H Wang Panxia P Luo Wenwei W Cai Sidong S Hu Yuehuai Y Guo Kaiteng K Wang Luping L Li Zhenzhen Z Wang Minghui M Zhang Xiaolei X Liu Peiqing P

British journal of pharmacology 20181209 3

<h4>Background and purpose</h4>Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy.<h4>Experimental approach</h4>Cellular hypertrophy in cultures of card ...[more]

PMID: 30414383

Similar Datasets

Project description:Adiponectin and miR-133a are key regulators in cardiac hypertrophy. However, whether APN has a potential effect on miR-133a remains unclear. In this study, we aimed to investigate whether APN could regulate miR-133a expression in Angiotensin II (Ang II) induced cardiac hypertrophy in vivo and in vitro. Lentiviral-mediated adiponectin treatment attenuated cardiac hypertrophy induced by Ang II infusion in male wistar rats as determined by reduced cell surface area and mRNA levels of atrial natriuretic peptide (ANF) and brain natriuretic peptide (BNP), also the reduced left ventricular end-diastolic posterior wall thickness (LVPWd) and end-diastolic interventricular septal thickness (IVSd). Meanwhile, APN elevated miR-133a level which was downregulated by Ang II. To further investigate the underlying molecular mechanisms, we treated neonatal rat ventricular myocytes (NRVMs) with recombinant rat APN before Ang II stimulation. Pretreating cells with recombinant APN promoted AMP-activated protein kinase (AMPK) phosphorylation and inhibited ERK activation. By using the inhibitor of AMPK or a lentiviral vector expressing AMPK short hairpin RNA (shRNA) cancelled the positive effect of APN on miR-133a. The ERK inhibitor PD98059 reversed the downregulation of miR-133a induced by Ang II. These results indicated that the AMPK activation and ERK inhibition were responsible for the positive effect of APN on miR-133a. Furthermore, adiponectin receptor 1 (AdipoR1) mRNA expression was inhibited by Ang II stimulation. The positive effects of APN on AMPK activation and miR-133a, and the inhibitory effect on ERK phosphorylation were inhibited in NRVMs transfected with lentiviral AdipoR1shRNA. In addition, APN depressed the elevated expression of connective tissue growth factor (CTGF), a direct target of miR-133a, through the AMPK pathway. Taken together, our data indicated that APN reversed miR-133a levels through AMPK activation, reduced ERK1/2 phosphorylation in cardiomyocytes stimulated with Ang II, revealing a previously undemonstrated and important link between APN and miR-133a.

Dataset Information

Sirtuin 1 represses PKC-? activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy.

Publications

Sirtuin 1 represses PKC-ζ activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets