TY - JOUR
T1 - mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart
AU - Vinciguerra, Manlio
AU - Santini, Maria Paola
AU - Martinez, Conception
AU - Pazienza, Valerio
AU - Claycomb, William C.
AU - Giuliani, Alessandro
AU - Rosenthal, Nadia
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
KW - Cardiomyocytes
KW - Insulin-like growth factor-1
KW - Oxidative stress
KW - Sirtuin-1
UR - http://www.scopus.com/inward/record.url?scp=84855860714&partnerID=8YFLogxK
U2 - 10.1111/j.1474-9726.2011.00766.x
DO - 10.1111/j.1474-9726.2011.00766.x
M3 - Article
C2 - 22051242
AN - SCOPUS:84855860714
SN - 1474-9718
VL - 11
SP - 139
EP - 149
JO - Aging Cell
JF - Aging Cell
IS - 1
ER -