Download cardiomyocyte-secreted acetylcholine is required for maintenance of

1241
Oral or Poster
Cat: Molecular Cardiology, Basic Research
CARDIOMYOCYTE-SECRETED ACETYLCHOLINE IS REQUIRED FOR
MAINTENANCE OF HOMEOSTASIS IN THE HEART
A. Roy1,2, W.C. Fields3, C. Rocha-Resende4, R.R. Resende5, S. Guatimosim4,
V.F. Prado1,2,6, R. Gros1,2,7, M.A. Prado1,2,6
1. Robarts Research Institute, London, Ontario, Canada
2. Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario,
Canada
3. Program in Neuroscience, The University of Western Ontario, London, Ontario, Canada
4. Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de
Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
5. Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de
Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
6. Department of Anatomy & Cell Biology, The University of Western Ontario, London, Ontario, Canada
7. Department of Medicine, The University of Western Ontario, London, Ontario, Canada
The parasympathetic nervous system plays an important role in regulating cardiac
function. Genetically modified mice with globally reduced expression of the vesicular
acetylcholine transporter (VAChT), the protein responsible for packaging acetylcholine
(ACh), develop significant ventricular dysfunction despite the fact that parasympathetic
innervation of ventricles is sparse. Recently, it has been proposed that rat cardiomyocytes
are able to synthesize and release ACh. Ventricular cardiomyocytes express prototypical
markers of the neuronal cholinergic system. Furthermore, cardiomyocyte-derived ACh is
secreted in a VAChT-dependent manner and protects isolated cardiomyocytes from the
hypertrophic response induced through hyperadrenergic stimulation. To test for the
physiological role of cardiomyocyte-derived ACh we used the Cre/loxP system to
genetically eliminate VAChT only in cardiomyocytes (cVAChT). Control experiments
indicate that parasympathetic nerves are spared of Cre-mediated recombination, while
cardiomyocytes in cVAChT mice show deletion of VAChT. Interestingly, 3 month-old
cVAChT mice present cardiomyocyte and cardiac hypertrophy. Additionally, these mice
display several signs of cellular stress as well as altered calcium handling. Furthermore,
an increase in heart rate under restraint is observed. Importantly, heart rate recovery
following acute exercise, a process dependent on cholinergic parasympathetic activity, is
delayed in cVAChT mice. These data suggest a novel mechanism for regulation of heart
rate wherein cardiomyocyte-derived ACh is involved in amplifying neuronal
parasympathetic signalling with functional consequences for the control of heart rate and
cardiac remodelling in vivo.
Funding: Heart and Stroke Foundation of Ontario