EGF Receptor Transactivation In GPCR-mediated Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$710,625.00
Summary
Soon after birth, the muscle cells of the human heart stop dividing and subsequent growth of the heart occurs through enlargement of pre-existing muscle cells in a process referred to as hypertrophy. This normal growth accounts for the difference in size between juvenile and adult human hearts. In certain people, heart cell growth is accelerated as a consequence of complex genetic, hormonal and environmental factors. In others, it occurs as an adaptive response to high blood pressure or damage-d ....Soon after birth, the muscle cells of the human heart stop dividing and subsequent growth of the heart occurs through enlargement of pre-existing muscle cells in a process referred to as hypertrophy. This normal growth accounts for the difference in size between juvenile and adult human hearts. In certain people, heart cell growth is accelerated as a consequence of complex genetic, hormonal and environmental factors. In others, it occurs as an adaptive response to high blood pressure or damage-disease of the heart muscle, such as occurs following a heart attack. As hearts grow inappropriately, they function less efficiently and eventually fail. Cardiac hypertrophy is therefore a major risk factor for heart failure and death. Hormones like adrenalin, angiotensin, and endothelin affect cells of the heart and blood vessels to regulate blood pressure and volume. In addition, these hormones also act directly on heart cells to cause growth, particularly during the accelerated phase associated with cardiac hypertrophy. One attribute shared by these hormones is that they act through G-protein coupled receptors (GPCRs), a superfamily of cell surface proteins. How binding of hormone to its specific GPCR triggers cell growth has been the focus of extensive research. Based on studies of angiotensin receptors in cultured muscle cells, we have observed that the growth action of angiotensin receptors requires them to first hijack another receptor - the epidermal growth factor receptor. By commandeering the EGF receptor, the angiotensin hormone in effect usurps growth-signalling pathways. This application proposes experiments that will investigate the mechanism and consequence of GPCRs stimulation of EGF receptors in heart cells and whole animals. By understanding the mechanism by which angiotensin promotes growth, better therapeutic regimens against abnormal growth of the heart during human cardiovascular disease will evolve.Read moreRead less
Muscle cells that constitute the bulk of the human heart do not divide but enlarge as we grow. Accelerated heart cell growth, as a consequence of heart damage or other factors, is a predictor of heart failure and early death. This application examines the cellular events that control heart growth in response to angiotensin, a hormone linked to heart failure. By understanding the mechanism by which angiotensin promotes growth, better therapies against human cardiovascular disease will evolve.