The primary long term goal of the proposed research is to investigate the mechanisms responsible for cardiovascular complications from cocaine abuse in AIDS patients. Serious cardiovascular complications due to cocaine abuse are well known; however, the molecular mechanisms have not been delineated. Cytokines play a significant role in the normal regulation of the function of endothelial cells and cardiac myocytes. There is growing evidence that the Tat protein of HIV- l can alter cellular gene expression and signal transduction pathways and can induce the formation of cytokines such as TNFalpha, and IL-1beta. Preliminary data demonstrate that TNFalpha can compromise cardiovascular function which is exacerbated in the presence of cocaine. We will therefore test the hypothesis that a combination of Tat and the cytokines (TNFalpha and IL- 1beta) with cocaine and its metabolites can produce cardiovascular complications in AIDS patients, by investigating the following specific aims: (l) to determine the effects of cocaine and its major metabolites in modulating the Ca2+, Na+ and K+ currents in isolated human cardiac myocytes in the presence and absence of TNFalpha or IL-1beta; (2) to investigate the modulatory effects of Tat protein and/or the inflammatory cytokines in the presence or absence of cocaine on integrin expression and integrin mediated events, i.e., endothelial cell migration and leucocyte adhesion to endothelial cells; (3) to assess the cardiovascular complications in mice acutely or chronically treated with cocaine and/or TNFalpha by monitoring the changes in: (a) systemic vascular resistance measured by systemic arterial pressure and cardiac output, (b) pulmonary vascular resistance determined by monitoring pulmonary arterial pressure and cardiac output, and (c) left ventricular contractility by measuring changes and the rate of change in the left ventricular pressure; and (4) to determine the role of Tat protein in modulating cardiovascular function. The tat transgenic and TNFalpha receptor knockout mouse models will be used to test the various parameters indicated under specific aim #3. The proposed studies will provide an in-depth understanding of the molecular mechanisms that may be responsible for the cocaine-induced cardiovascular complications in the presence of HIV infection. The unifying theme of the proposal is to define the role of Tat and the inflammatory cytokines in modulating the cocaine induced cardiotoxic effects that have been observed in patients with AIDS.
