title: The TRPA1 channel is a cardiac target of mIGF-1/SIRT1 signaling.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Medical Sciences, IRCCS Scientific Institute "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy;
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.affiliation: Department of Anatomy, University of Malta, Msida, Malta; Department of Forensic Pathology, University of Foggia, Foggia, Italy;
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Pomara
authors.affiliation: Department of Experimental Medicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.affiliation: Molecular Biotechnology Center, University of Turin, Turin, Italy;
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.affiliation: Molecular Biotechnology Center, University of Turin, Turin, Italy;
authors.forename: Matteo
authors.initials: M
authors.lastname: Carrara
authors.affiliation: Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS Scientific Institute "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy; and.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.affiliation: Division of Gastroenterology, Department of Medical Sciences, IRCCS Scientific Institute "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Division of Medicine, University College London, London, United Kingdom. m.vinciguerra@operapadrepio.it.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D011687:Purines; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: heart; insulin-like growth factor-1; sirtuin 1; transient receptor potential cation channel, subfamily A, member 1