mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart |
| |
Authors: | Vinciguerra Manlio Santini Maria Paola Martinez Conception Pazienza Valerio Claycomb William C Giuliani Alessandro Rosenthal Nadia |
| |
Affiliation: | European Molecular Biology Laboratory-Mouse Biology Unit, Monterotondo-Scalo, Roma, Italy. Manlio.Vinciguerra@embl.it |
| |
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. |
| |
Keywords: | insulin‐like growth factor‐1 Sirtuin‐1 oxidative stress cardiomyocytes |
本文献已被 PubMed 等数据库收录! |
|