Endothelial Fibrinolytic Capacity Is Impaired in HIV-1-infected Men
Michael Mestek*, B Stauffer, C Westby, B Weil, G Van Guilder, J Greiner, E Connick, and C Desouza
Univ of Colorado, Boulder and Denver, US
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
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.