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

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