Both HIV-1 infection and active cocaine use are associated with a myriad of cardiovascular diseases including accelerated atherosclerosis. Cocaine mediates some effects via the catecholamines, while both HIV-1 infection and cocaine use are associated with immunological dysregulation. Since atherosclerosis appears to be mediated immunologically, we postulate that inflammatory cytokines and nitrite secreted by mast cells and endothelial cells activated by cocaine and HIV infection modulate macrophage function and hence atherogenesis. We will answer the following questions: 1) Are activated human mast cells and coronary endothelial cells capable of expressing factors that mediate atherogenesis, namely specific chemokines (Interleukin-8 [IL-8], monocyte chemotactic protein-1 [MCP-1]), cytokines regulating the acute phase response (IL-6 and tumor necrosis factor alpha [TNF-alpha]) and macrophage colony stimulating factor [M-CSF]? Is there activation of protein kinase C (PKC) and nuclear factor-kB, (NF-kappaB)? Is this activation modulated by inhibitors of PKC and NF-kappaB? 2) Do cocaine and catecholamines alone or in combination with the HIV-1 proteins (gp 120 and tat) induce human coronary endothelial and mast cell activation resulting in induction of PKC and NF-kappaB and the elaboration of nitric oxide and tryptase, IL-6, IL-8, TNF-alpha, MCP-1 and M-CSF? Is this activation affected by inhibitors of PKC and NF-kappaB? 3) Do patients with HIV-1 infection have higher plasma levels of nitric oxide and tryptase, IL-6, IL-8, TNF-alpha, MCP-1 and M-CSF? Do these levels differ in patients with HIV-1 infection with or without concomitant/active cocaine use? Does acute cocaine use enhance levels of these factors? Are these correlated with disease severity or heart disease occurrence? ,4) Do supernatants of mast cells and endothelial cells (activated by cocaine, norepinephrine, HIV-gp12O or tat) or sera of patients (with HIV- 1 infection, with or without concomitant/active cocaine use) contain factor/s that modulate macrophage function? Can antioxidants or NF-kappaB inhibitors modulate this process? This study will shed light on the pathogenesis of cardiovascular disease in a HIV-infected and/or cocaine-using population with multiple risk factors for immune-mediated vascular inflammation.
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