Ca2+ and Calmodulin Signaling in the Cardiac Myocyte under Hypertensive Stress

High blood pressure (hypertension) is a potent trigger for cardiac hypertrophy and heart failure. However, the cellular and molecular mechanisms linking hypertension to hypertrophy remain unclear. Our recent studies provide a possible clue to the identity of this molecular link. In an animal model for human hypertension and heart failure, we found that the calcium (Ca2+) signal increases just as hypertension develops, long before hypertrophy occurs. This increase in the Ca2+ signal is important because it can explain how the heart is able to contract more forcefully to maintain cardiac output in the face of increasing blood pressure. But what is the molecular link between hypertension and the Ca2+ signal increase? We found that the level of calmodulin (CaM) molecules increases as hypertension develops just as the Ca2+ signal is increasing. The discovery that CaM levels increases at the early phase of hypertension is very important because CaM has been shown to affect a variety of processes that can lead to an increased Ca2+ signal. CaM is also known to activate a number of signaling pathways including Ca2+-calmodulin dependent protein kinases, calcineurin, and mitogen-activated protein kinases. Activation of these molecules has been shown to lead to cardiac hypertrophy and heart failure. Like an increased Ca2+ signal, cardiac hypertrophy (growth of the heart) serves as a mechanism to maintain cardiac output as blood pressure increases. Thus our preliminary research suggests that CaM is central to understanding both the short term (increased Ca2+ signal) and long term (hypertrophy) compensatory responses to hypertension. The research proposed here tests the link between changing CaM levels and altered Ca2+ signaling and tests whether preventing hypertension prevents the increase in CaM levels. This research is my first step towards a long-term goal to identify the cellular and molecular mechanisms responsible for the induction of hypertensive heart disease, so to provide strategies for early pharmaceutical intervention.