title: Cardiomyocyte-secreted acetylcholine is required for maintenance of homeostasis in the heart.
abstract: Heart activity and long-term function are regulated by the sympathetic and parasympathetic branches of the nervous system. Parasympathetic neurons have received increased attention recently because acetylcholine (ACh) has been shown to play protective roles in heart disease. However, parasympathetic innervation is sparse in the heart, raising the question of how cholinergic signaling regulates cardiomyocytes. We hypothesized that non-neuronal secretion of ACh from cardiomyocytes plays a role in cholinergic regulation of cardiac activity. To test this possibility, we eliminated secretion of ACh exclusively from cardiomyocytes by targeting the vesicular acetylcholine transporter (VAChT). We find that lack of cardiomyocyte-secreted ACh disturbs the regulation of cardiac activity and causes cardiomyocyte remodeling. Mutant mice present normal hemodynamic parameters under nonstressful conditions; however, following exercise, their heart rate response is increased. Moreover, hearts from mutant mice present increased oxidative stress, altered calcium signaling, remodeling, and hypertrophy. Hence, without cardiomyocyte-derived ACh secretion, hearts from mutant mice show signs of imbalanced autonomic activity consistent with decreased cholinergic drive. These unexpected results suggest that cardiomyocyte-derived ACh is required for maintenance of cardiac homeostasis and regulates critical signaling pathways necessary to maintain normal heart activity. We propose that this non-neuronal source of ACh boosts parasympathetic cholinergic signaling to counterbalance sympathetic activity regulating multiple aspects of heart physiology.
authors.affiliation: 1Robarts Research Institute, 100 Perth Dr., London, Ontario, N6A 5K8, Canada. M.A.M.P., mprado@robarts.ca.
authors.forename: Ashbeel
authors.initials: A
authors.lastname: Roy
authors.forename: William C
authors.initials: WC
authors.lastname: Fields
authors.forename: Cibele
authors.initials: C
authors.lastname: Rocha-Resende
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Resende
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D006321:Heart / Q000502:physiology; D006439:Hemodynamics; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress; D005082:Physical Exertion; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D000109:Acetylcholine
keywords: VAChT; autonomic function; cardiac hypertrophy; cardiac remodeling; choline acetyltransferase; parasympathetic activity
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