Activation of Bnip3 in tobacco-induced heart disease
Initial Award Abstract
Cigarette smoking is a well established risk factor for the development of cardiovascular diseases including arrythmias, myocardial infarction and stroke. The mechanism for the increased risk of developing cardiovascular disease is not well understood, but is likely to include the absorption of tobacco smoke constituents which will affect function of the cells in the heart. Cigarette smoke is known to contain many chemicals that can induce cell death. In recent years, it has become clear that a major contributing factor to the initiation and progression of cardiovascular disease is the death of cells in the heart via a process called apoptosis. Apoptosis is a highly regulated, energy-dependent suicide program in which the cell activates a signaling cascade leading to cell death. Importantly, heart muscle cells (cardiac myocytes) are terminally differentiated; once destroyed they are not replaced. Consequently, with fewer myocytes the ability of the myocardium to sustain contractile function is reduced. Exposure to tobacco smoke has been reported to cause apoptosis in various cells; thus, increased apoptosis in the myocardium may increase the risk of developing heart failure.
The goal of this proposal is to investigate the role of Bnip3 in tobacco-induced cardiovascular disease. Bnip3 is a pro-apoptotic protein that causes apoptosis of cells when activated. The level of this protein has been shown to increase in animal models of acute ischemia and heart failure. Increased level of Bnip3 has been shown to lead to cell death. This proposal intends to investigate the role of the pro-apoptotic protein Bnip3 in tobacco smoke-induced apoptosis in heart cells. We will test the hypothesis that exposure to cigarette smoke leads to an up-regulaion of Bnip3 in the heart, increasing the likelyhood of developing heart failure. We also plan to investigate how Bnip3 activity is regulated in the heart and elucidate the mechanism(s) by which Bnip3 causes cell death.
It is important to elucidate the pathways activated by tobacco smoke which lead to cell death. Increased understanding of the apoptotic process may lead to the identification of new therapeutic targets. The ultimate goal is to understand how tobacco smoke increased the risk of developing cardiovascular disease and apply this knowledge to the prevention and treatment of heart disease. |