Background: Myocardial inflammation with pericardial effusions leading to cardiac tamponade and cardiomyopathies are a frequent finding in AIDS patients. Up-regulation of microvascular endothelial cell adhesion molecule (CAM) expression by oxidants and/or circulating cytokines produces a hyperadhesive endothelium that preferentially sequesters leukocytes and contributes to the inflammatory process. Further secretion of oxidants, pro-inflammatory mediators and/or proteases by these cells causes alterations to the endothelial permeability barrier, setting up a cascade of events that end in cardiomyocyte dysfunction and cardiac failure. The cardiac pathologies in AIDS patients occur even in the absence of known opportunistic infections or direct infection by HIV, suggesting the existence of a soluble factor, either of viral of cellular origin. This soluble factor may be the HIV-1 Tat protein. It is proposed that release of the soluble HIV-1 Tat regulatory protein from infected cells and its uptake by uninfected cells increases oxidant stress, affects NF-kB activation and elevates CAM levels, which sequesters leukocytes and depresses cardiac cell function. The mechanisms underlying this process relates to inhibition of the target cell's antioxidant enzymes Mn-SOD and is reflected by a perturbed GSH/GSSG ratio. Therefore, the specific aims are to test the hypotheses that 1) Tat-dependent Mn-SOD inhibition of cardiac microvascular endothelial cells increases oxidant stress 2) that Tat-mediated oxidants stress results in CAM up-regulation, possibly via NF-kB and/or AP-1 activation 3) that Tat increases cytokine secretion 4) that these Tat-mediated alterations increase leukocyte-endothelial cell interactions 5) that Tat also mediates increases in vascular permeability. All of these events converge to affect the integrity of cardiac endothelium and may therefore result in some of the cardiovascular abnormalities seen in AIDS. The effect of Tat on cardiac endothelial cell, and/or leukocyte function will be evaluated in cells isolated from human sources and from Tat-transgenic mice. The proposed research addresses one of the important questions regarding the etiology of cardiovascular complications in AIDS: why is there evidence of myocarditis, yet very little evidence of a pathogenic viral, bacterial, or fungal agent? Tat-mediated oxidative stress may be an important contributor to the cardiac inflammation seen in these patients.
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