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PKC\u2010\u03b6 can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)\u2010trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1\u2010PKC\u2010\u03b6 signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague\u2010Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC\u2010\u03b6 was investigated by co\u2010immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad\u2010sirtuin1 transfection. A model of cardiac hypertrophy in Sprague\u2010Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Overexpression of PKC\u2010\u03b6 led to cardiac hypertrophy and increased activity of NF\u2010\u03baB, ERK1\/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC\u2010\u03b6, hindered its binding to phosphoinositide\u2010dependent kinase 1 and inhibited PKC\u2010\u03b6 phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC\u2010\u03b6' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Sirtuin1 is an endogenous negative regulator for PKC\u2010\u03b6 and mediates its activity <jats:italic>via<\/jats:italic> regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1\u2010PKC\u2010\u03b6 signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14538","type":"journal-article","created":{"date-parts":[[2018,11,10]],"date-time":"2018-11-10T21:14:56Z","timestamp":1541884496000},"page":"416-435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Sirtuin 1 represses PKC\u2010\u03b6 activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy"],"prefix":"10.1111","volume":"176","author":[{"given":"Jingyan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation Sun Yat\u2010sen University  Guangzhou Guangdong 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