Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity

Abstract: Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulina??like growth factora??1(IGFa??1) is a peptide hormone with a complex posta??transcriptional regulation, generating distinct isoforms. Locally actingIGFa??1 isoform (mIGFa??1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderateoverexpression of the NAD+a??dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known topromote lifespan extension and to protect from metabolic challenges. Circulating IGFa??1 and SirT1 play antagonizingbiological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, howdifferent IGFa??1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally actingmIGFa??1 increases SirT1 expression/activity, whereas circulating IGFa??1 isoform does not affect it, in cultured HLa??1 andneonatal cardiomyocytes. mIGFa??1a??induced SirT1 activity exerts protection against angiotensin II (Ang II)a??triggeredhypertrophy and against paraquat (PQ) and Ang IIa??induced oxidative stress. Conversely, circulating IGFa??1 triggered itselfoxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardioa??protective genes (adiponectin, UCPa??1 and MTa??2) were increased specifically in mIGFa??1a??overexpressing cardiomyocytes, in a SirT1a??dependent fashion. Thus, mIGFa??1protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiactherapeutic.