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

Article date: February 2019

By: Jingyan Li, Junying Huang, Jing Lu, Zhen Guo, Zhuoming Li, Hui Gao, Panxia Wang, Wenwei Luo, Sidong Cai, Yuehuai Hu, Kaiteng Guo, Luping Wang, Zhenzhen Li, Minghui Wang, Xiaolei Zhang, Peiqing Liu in Volume 176, Issue 3, pages 416-435

Background and Purpose

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.

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‐ζ 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‐ζ led to cardiac hypertrophy and increased activity of NF‐κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC‐ζ, hindered its binding to phosphoinositide‐dependent kinase 1 and inhibited PKC‐ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC‐ζ' 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‐ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1‐PKC‐ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.

DOI: 10.1111/bph.14538

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