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

Abstract

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.

PKC and PKN in heart disease

“…While the biological functions of PKC phosphorylation have long been characterized, it recently emerged that at least one PKC isozyme, PKCζ, may also undergo posttranslational modification by lysine-acetylation [54]. The authors of this study found that the deacetylase SIRT1 represses PKCζ activation by inhibiting its initial PDK1 mediated phosphorylation.…”

The role of post‐translational modifications in cardiac hypertrophy

“…Acetylation and trimethylation on H3K27 play opposing roles at the promoter regions of genes involved in cardiac hypertrophy . A previous study has shown that SIRT1 attenuated the PKC‐ζ activity via mediating the interplay of acetylation and phosphorylation in cardiac hypertrophy (Figure ). In conclusion, these findings suggest that crosstalk between different pairs of PTMs is essential for cardiac function.…”

“…In addition, cardiomyocyte hypertrophy was attenuated by transcription factor 3 (ATF3), binding with the Map2K3 promoter, resulting in recruiting HDAC1 and suppressing MAP2K3‐p38 Signalling . Furthermore, the class III HDAC, sirtuin 1 (SITR1), reportedly prevented cardiomyocyte hypertrophy by negatively regulating the acetylation and phosphorylation levels of protein kinase C‐ζ (Table ) . Likewise, Class I HDACs attenuated cardiac hypertrophy by repressing the TSC2‐dependent mammalian target of rapamycin pathway .…”

Sorting nexin 3 induces myocardial injury via promoting retromer-dependent nuclear trafficking of STAT3

“…1a and b). Similarly, the mRNA and protein levels of SNX3 were clearly induced in the myocardium of mouse HF model by subcutaneous (s.c.) injection of ISO (3 mg/kg/day, a classic hypertrophic agonist [30][31][32] ) for four weeks (Supplementary Figure S1b-d). These results suggest that SNX3 was associated with cardiac hypertrophy and HF in human and mice.…”

“…Experimental animals were housed, bred, and maintained in the speci c pathogen-free (SPF) facility of the Experimental Animal Center of Sun Yat-sen University. As we previously described 30 , the transthoracic 2D-guided M-mode echocardiography (such as heart function and global cardiac volumes) was assessed using by a Technos MPX ultrasound system (ESAOTE, SpAESAOTE SpA, Italy) equipped with an 40-MHz scan probe. The Vevo 2100 imaging software was used for measurements and calculations.…”