Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.
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.
Lara
Aline
A
Department of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG CEP 31270-901, Brazil.
Damasceno
Denis D
DD
Pires
Rita
R
Gros
Robert
R
Gomes
Enéas R
ER
Gavioli
Mariana
M
Lima
Ricardo F
RF
Guimarães
Diogo
D
Lima
Patricia
P
Bueno
Carlos Roberto
CR
Vasconcelos
Anilton
A
Roman-Campos
Danilo
D
Menezes
Cristiane A S
CA
Sirvente
Raquel A
RA
Salemi
Vera M
VM
Mady
Charles
C
Caron
Marc G
MG
Ferreira
Anderson J
AJ
Brum
Patricia C
PC
Resende
Rodrigo R
RR
Cruz
Jader S
JS
Gomez
Marcus Vinicius
MV
Prado
Vania F
VF
de Almeida
Alvair P
AP
Prado
Marco A M
MA
Guatimosim
Silvia
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D018678:Cholinergic Agents / Q000378:metabolism*; D004452:Echocardiography; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D054969:Primary Dysautonomias / Q000503:physiopathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism
D018678:Cholinergic Agents; D043562:Receptors, G-Protein-Coupled; D050494:Vesicular Acetylcholine Transport Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium