Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation.
OBJECTIVE
A complex set of metabolic and inflammatory processes are involved in the development of cardiac hypertrophy. Accumulating evidence indicates an important role for Sirt1 in cardiac function, whereas peroxisome proliferator-activated receptor-α (PPARα) is a master controller of cardiac lipid metabolism and plays a protective role on cardiac hypertrophy. The objective of the present study was to explore the relationships between Sirt1 and PPARα in the control of hypertrophy, metabolism, and inflammation processes in the heart.


RESULTS
Neonatal cardiomyocytes (NCMs) were used for studies in vitro. Both the activation of Sirt1 with resveratrol (RSV) and overexpression of Sirt1 inhibited phenylephrine (PE)-induced NCM hypertrophy and prevented PE-induced down-regulation of fatty acid oxidation genes. Sirt1 also inhibited the PE-induced increase in mRNA levels of the pro-inflammatory cytokine monocyte chemoattractant protein-1 in NCMs and blocked the enhanced nuclear factor-κB (NF-κB) activity associated with exposure to PE. Importantly, inhibition of PPARα suppressed the beneficial effects of Sirt1 on hypertrophy, fatty acid metabolism, and inflammation. Co-immunoprecipitation studies revealed that overexpression of Sirt1 enhanced PPARα binding to the p65 subunit of NF-κB and led to p65-deacetylation in NCMs. Moreover, Sirt1 overexpression led to the deacetylation of the PPARα co-activator PGC-1α. Consistent with these observations in vitro, isoproterenol-induced cardiac hypertrophy, metabolic dysregulation, and inflammation in vivo were prevented by RSV in wild-type mice but not in PPARα-null mice.


CONCLUSIONS
Collectively, these findings reveal a major involvement of the Sirt1-PPARα interaction in the protective role of Sirt1 against cardiac hypertrophy.
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Avda Diagonal 645, Barcelona E-08028, Spain. aplanavila@ub.edu
Ana
A
Planavila
Roser
R
Iglesias
Marta
M
Giralt
Francesc
F
Villarroya
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000276:immunology; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D050356:Lipid Metabolism / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D009205:Myocarditis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002316:Cardiotonic Agents; D005227:Fatty Acids; D016328:NF-kappa B; D047493:PPAR alpha; D013267:Stilbenes; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol