Background:  Rates of atherosclerotic lesion development, myocardial infarction and restenosis are higher in HIV-1-seropositive adults than the general population. The mechanisms responsible for this heightened cardiovascular risk are not fully understood. The capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of the fibrinolytic system, is a key endogenous defense mechanism against intravascular fibrin deposition and thrombosis. We tested the hypotheses that the capacity of the vascular endothelium to release t-PA is reduced in HIV-1-seropositive treatment-naive compared with HIV-1-seronegative adults; and that the decrease in endothelial t-PA release in HIV-1-infected adults is due, in part, to increased oxidative stress.

Methods:  We studied 10 HIV-1-seronegative (age 36±3 years) and 7 HIV-1-seropositive treatment-naive (34±2 years) men. All subjects were free of overt metabolic and cardiovascular disease. Net endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK; 125 to 500 ng/min) and sodium nitroprusside (2.0 to 8.0 µg/min). BK was selected to stimulate endothelial t-PA release due to its effectiveness at eliciting a local and rapid response. Sodium nitroprusside was required to establish that any observed differences in t-PA release to BK were not due to increased blood flow related shear stress. To determine the effects of oxidative stress on endothelial t-PA release, the BK dose response curves were repeated with a co-infusion of the antioxidant vitamin C (24 mg/min). Group differences were determined by repeated measures ANOVA.

Results:  Net endothelial t-PA release was significantly lower (~40%; p <0.05) in HIV-1-seropositive (from –0.14±1.2 to 47.2±10.9 ng/100 mL tissue/min) compared with seronegative (–0.43±0.9 to 75.4±11.0 ng/100 mL tissue/min) men. Vitamin C markedly increased (~30%; p <0.05) t-PA release in response to BK in the HIV-1-seropositive (–1.4±0.5 to 60.4±9.1 ng/100 mL tissue/min) but not seronegative (–1.3±0.9 to 73.4±11.0 ng/100 mL tissue/min) men. There was no effect of sodium nitroprusside on t-PA release in either group.

Conclusions:  The capacity of the endothelium to release t-PA is blunted in untreated HIV-1-seropositive compared with seronegative men and this dysfunction is due, in part, to oxidative stress. Diminished endothelial fibrinolytic capacity may contribute to the increased risk of atherothrombotic events in HIV-1-infected adults.