Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions

FASEB J. 2016 Feb;30(2):688-701. doi: 10.1096/fj.15-277046. Epub 2015 Oct 19.


Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24 ± 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure.

Keywords: VAChT; choline acetyltransferase; heart disease; heart failure; nonneuronal acetylcholine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Cells, Cultured
  • Choline O-Acetyltransferase / genetics
  • Choline O-Acetyltransferase / metabolism*
  • Gene Expression Regulation, Enzymologic / physiology
  • Heart Failure / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ventricular Remodeling / physiology*
  • Vesicular Acetylcholine Transport Proteins / genetics
  • Vesicular Acetylcholine Transport Proteins / metabolism*


  • RNA, Messenger
  • Vesicular Acetylcholine Transport Proteins
  • Choline O-Acetyltransferase
  • Acetylcholine