期刊
FASEB JOURNAL
卷 27, 期 12, 页码 5072-5082出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-238279
关键词
cardiac remodeling; VAChT; choline acetyltransferase; parasympathetic activity; cardiac hypertrophy; autonomic function
资金
- Heart and Stroke Foundation of Ontario [NA6656, G-13-0002843]
- Canadian Institutes for Health Research [MOP-82756, MOP-89919]
- Canadian Foundation for Innovation
- Ontario Research Fund
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq
- Brazil)
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG
- Brazil)
- U.S. National Institutes of Health from the Fogarty International Center [R03TW008425]
- Ontario Graduate Scholarship
- New Investigator Award from the Heart and Stroke Foundation of Canada
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.
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