Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.
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2010
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Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In
contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By
using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter
(VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of
altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis
of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant
mice have decreased left ventricle function associated with altered calcium handling. Gene expression was
analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that
VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This
phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor
pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct
evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic
alterations that contribute to heart dysfunction.
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GOMES, A. A. L. G. et al. Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure. Molecular and Cellular Biology, v. 30, p. 1746-1756, 2010. Disponível em: <http://mcb.asm.org/content/30/7/1746.full>. Acesso em: 19 fev. 2017.