Institut de cardiologie de Montréal
Cardiac hypertrophy, a major cause of heart diseases such as myocardial infarction and cardiac arrhythmias, occurs when the heart is continuously exposed to increased load and/or neurohormonal factors including endothelin-1. Hypertrophic stimuli activate both the ERK1/2 and p38 MAP kinase pathways. Upon activation, p38mapk, p42mapk and p44mapk translocate to the nucleus and induce changes in the pattern of gene expression. A combination of in vivo and in vitro biochemical and pharmacological approaches are being employed to study the organization, specificity and roles of p42/44 and p38 map kinase signalling and how these relate to changes in cardiac growth and function evoked by hypertrophic stimuli. In addition, the roles of the endothelin receptor subtypes ETA and ETB, located at the cell surface and on the nuclear membrane, are being examined. This information should further the understanding of both signal transduction in the healthy heart and the defects which impair the ability of the heart to function in a normal manner, thereby identifying suitable targets for pharmacological intervention in the treatment of heart diseases.
GPCR signaling in the nuclear envelope
- Boivin, B., Chevalier, D., Villeneuve, L.R., Rousseau, E., and Allen, B.G. (2003) Functional endothelin receptors are present on nuclei in cardiac ventricular myocytes. J. Biol. Chem. 278, 29153-29163.
- Boivin, B., Lavoie, C., Vaniotis, G., Baragli, A., Villeneuve, L.R., Ethier, N., Trieu, P., Allen, B.G., and Hébert, T.E. (2006) Functional b-adrenergic receptor signalling on nuclear membranes in adult rat and mouse ventricular cardiomyocytes. Cardiovasc. Res. 71, 69-78.
- Boivin, B., Vanoitis, G., Allen, B.G., and Hébert, T. (2008) G protein-coupled receptors in and on the cell nucleus: a new signalling paradigm? J. Rec Sig. Trans. 28, 15-28.
- Tadevosyan, A., Maguy, A., Villeneuve, L.R., Babin, J., Bonnefoy, A., Allen, B.G., and Nattel S. (2010) A Potential role for nuclear-delimited signaling via nuclear-envelope angiotensin receptors in the control of cardiac gene expression. J. Biol. Chem. 285, 22338-22349.
- Vaniotis, G., Del Duca, D., Trou, P., Rohlicek, C.V., Hébert, T.E., and Allen, B.G. (2011) Regulation of gene expression by b-adrenergic receptors on the nuclear envelope. Cell. Signal. 23, 89-98.
p38 MAP kinase signaling in the heart
- Chevalier, D. and Allen, B.G. (2000) Two distinct forms of MAPKAP kinase-2 in adult cardiac ventricular myocytes. Biochemistry 39, 6145-6156.
- Dingar, D., Benoit, M.J., Mamarbachi, A.M., Villeneuve, L.R., Gillis, M.A., Grandy, S., Gaestel, M., Fiset, C., and Allen, B.G. (2010) Characterization of the expression and regulation of MK5 in the murine ventricular myocardium. Cell. Signal. 22, 1063-1075.
- Moïse, N., Dingar, D., Mamarbachi, A.M., Villeneuve, L.R., Farhat, N., Gaestel, M., Khairallah, M., and Allen, B.G. (2010) Characterization of a novel MK3 splice variant in heart. Cell. Signal. 22, 1502-1512.
- Dingar, D., Merlen, C., Grandy, S., Gillis, M.A., Villeneuve, L.R., Mamarbachi, A.M., Fiset, C., and Allen, B.G. (2010) Expression and localization of p38 MAP kinase isoforms in the mouse heart. Cell. Signal. 22, 1634-1644.