Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity.
Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD(+)-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic.
Vinciguerra
Manlio
M
European Molecular Biology Laboratory-Mouse Biology Unit, Campus A. Buzzati-Traverso, Monterotondo-Scalo, Rome 00016, Italy. Manlio.Vinciguerra@embl.it
Santini
Maria Paola
MP
Claycomb
William C
WC
Ladurner
Andreas G
AG
Rosenthal
Nadia
N
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015870:Gene Expression; D005786:Gene Expression Regulation; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D020033:Protein Isoforms; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; C447939:SIRT1 protein, human; D056564:Sirtuin 1
IGF-1; SirT1; cardiomyocytes; cell hypertrophy; oxidative stress