The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy
Yang Guo,
Ze-Yan Yu,
Jianxin Wu,
Hutao Gong,
Scott Kesteven,
Siiri E Iismaa,
Andrea Y Chan,
Sara Holman,
Silvia Pinto,
Andy Pironet,
Charles D Cox,
Robert M Graham,
Rudi Vennekens,
Michael P Feneley,
Boris Martinac
Affiliations
Yang Guo
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia; Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Ze-Yan Yu
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia; Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Jianxin Wu
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia
Hutao Gong
Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia
Scott Kesteven
Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Siiri E Iismaa
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Andrea Y Chan
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia
Sara Holman
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia
Silvia Pinto
Laboratory of Ion Channel Research, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Katholieke Universiteit Leuven, Leuven, Belgium
Andy Pironet
Laboratory of Ion Channel Research, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Katholieke Universiteit Leuven, Leuven, Belgium
Charles D Cox
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Robert M Graham
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Rudi Vennekens
Laboratory of Ion Channel Research, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Katholieke Universiteit Leuven, Leuven, Belgium
Michael P Feneley
Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; Department of Cardiology, St Vincent’s Hospital, Sydney, Australia
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.
