title: mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart.
abstract: Oxidative stress contributes to the pathogenesis of aging-associated heart failure. Among various signaling pathways mediating oxidative stress, the NAD(+) -dependent protein deacetylase SirT1 has been implicated in the protection of heart muscle. Expression of a locally acting insulin-like growth factor-1 (IGF-1) propeptide (mIGF-1) helps the heart to recover from infarct and enhances SirT1 expression in cardiomyocytes (CM) in vitro, exerting protection from hypertrophic and oxidative stresses. To study the role of mIGF-1/SirT1 signaling in vivo, we generated cardiac-specific mIGF-1 transgenic mice in which SirT1 was depleted from adult CM in a tamoxifen-inducible and conditional fashion. Analysis of these mice confirmed that mIGF-1-induced SirT1 activity is necessary to protect the heart from paraquat (PQ)-induced oxidative stress and lethality. In cultured CM, mIGF-1 increases SirT1 expression through a c-Jun NH(2)-terminal protein kinase 1 (JNK1)-dependent signaling mechanism. Thus, mIGF-1 protects the heart from oxidative stress via SirT1/JNK1 activity, suggesting new avenues for cardiac therapy during aging and heart failure.
authors: European Molecular Biology Laboratory-Mouse Biology Unit, Monterotondo-Scalo, Roma, Italy. Manlio.Vinciguerra@embl.it
authors: Manlio
authors: M
authors: Vinciguerra
authors: Maria Paola
authors: MP
authors: Santini
authors: Conception
authors: C
authors: Martinez
authors: Valerio
authors: V
authors: Pazienza
authors: William C
authors: WC
authors: Claycomb
authors: Alessandro
authors: A
authors: Giuliani
authors: Nadia
authors: N
authors: Rosenthal
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D048055:Mitogen-Activated Protein Kinase 8; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D010269:Paraquat