mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart

Manlio Vinciguerra, Maria Paola Santini, Conception Martinez, Valerio Pazienza, William C. Claycomb, Alessandro Giuliani, Nadia Rosenthal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)139-149
Number of pages11
JournalAging Cell
Volume11
Issue number1
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Cardiomyocytes
  • Insulin-like growth factor-1
  • Oxidative stress
  • Sirtuin-1

ASJC Scopus subject areas

  • Cell Biology
  • Ageing

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