TRPA1 channel is a cardiac target of mIGF-1/SIRT1 signaling.

Abstract

Cardiac overexpression of locally acting insulin growth factor isoform (mIGF-1) and the consequent downstream activation of NAD+-dependent protein deacetylase SIRT1 trigger potent cardiac anti-oxidative and anti-hypertrophic effects. TRPA1 belongs to the transient receptor potential (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. Using a genomic screening in mice hearts, we found here 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 the cardiomyocytes and non cardiomyocyte cells. In wild type mice, SIRT1 occupies TRPA1 promoter inhibiting its expression, whereas in presence of cardiac mIGF-1 transgene, SIRT1 is displaced from TRPA1 promoter, leading to an increase in its expression. Cardiac specific ablation of SIRT1 (CKO) in mIGF-1 Tg mice paradoxically did not increase TRPA1 expression. We recently reported a systemic "hormetic" effect in mIGF-1 Tg mice, a mild hypertension, which was depleted upon SIRT1 CKO. 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.