Bolasco G.,European Molecular Biology Laboratory EMBL Mouse Biology Unit |
Calogero R.,University of Turin |
Carrara M.,University of Turin |
Al Banchaabouchi M.,European Molecular Biology Laboratory EMBL Mouse Biology Unit |
And 4 more authors.
Aging | Year: 2012
Locally acting insulin growth factor isoform (mIGF-1) and the NAD+-dependent protein deacetylase SIRT1 are implicated in life and health span. Heart failure is associated with aging and is a major cause of death. mIGF-1 protects the heart from oxidative stresses via SIRT1. SIRT1 subcellular localization and its genomic regulation by mIGF-1 are unknown. We show here that SIRT1 is located in the nuclei of a significant fraction of cardiomyocytes. Using high throughput sequencing approaches in mIGF-1 transgenic mice, we identified new targets of the mIGF-1/SIRT1 signaling. In addition to its potent cardioprotective properties, cardiac-restricted mIGF-1 transgene induced systemic changes such as high blood pressure, leukocytosis and an enhanced fear response, in a SIRT1-dependent manner. Cardiac mIGF-1/SIRT1 signaling may thus modulate disparate systemic functions. © Bolasco et al. Source
Pazienza V.,IRCCS Scientific Institute Casa Sollievo della Sofferenza |
Pomara C.,University of Malta |
Pomara C.,University of Foggia |
Cappello F.,University of Palermo |
And 7 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2014
Cardiac overexpression of locally acting muscle-restricted (m)IGF-1 and the consequent downstream activation of NAD -dependent protein deacetylase sirtuin 1 (SIRT1) trigger potent cardiac antioxidative and antihypertrophic effects. Transient receptor potential (TRP) cation channel A1 (TRPA1) belongs to the TRP ion channel family of molecular detectors of thermal and chemical stimuli that activate sensory neurons to produce pain. Recently, it has been shown that TRPA1 activity influences blood pressure, but the significance of TRPA1 in the cardiovascular system remains elusive. In the present work, using genomic screening in mouse hearts, we found that TRPA1 is a target of mIGF-1/SIRT1 signaling. TRPA1 expression is increased in the heart of cardiac-restricted mIGF-1 transgenic (Tg) mice, both in cardiomyocytes and noncardiomyocytes. In wild-type mice, SIRT1 occupied the TRPA1 promoter, inhibiting its expression, whereas in the presence of the cardiac mIGF-1 transgene, SIRT1 was displaced from the TRPA1 promoter, leading to an increase in its expression. Cardiac-specific ablation of SIRT1 (cardiac-specific knockout) in mIGF-1 Tg mice paradoxically did not increase TRPA1 expression. We have recently reported a systemic “hormetic” effect in mIGF-1 Tg mice, mild hypertension, which was depleted upon cardiac-specific knockout of SIRT1. Administration of the selective TRPA1 antagonist HC-030031 to mIGF-1 Tg mice restored blood pressure to basal levels. We identified TRPA1 as a functional target of the cardiac mIGF-1/SIRT1 signaling pathway, which may have pharmacological implications for the management of cardiovascular stress. © 2014 the American Physiological Society. Source