HIV gp120 induces endothelial dysfunction in tumour necrosis factor-α-activated porcine and human endothelial cells

The aim of this study was to determine direct effects and potential molecular mechanisms of HIV gp120, a viral envelope glycoprotein, on endothelial function. Fresh porcine coronary artery rings and human coronary artery endothelial cells (HCAECs) were treated with recombinant HIV gp120 for 16 h with or without pretreatment with tumour necrosis factor-alpha (TNF-alpha) (8 h). With a myograph tension analysis, HIV gp120 with TNF-alpha pretreatment significantly decreased endothelium-dependent vasorelaxation in response to bradykinin in porcine coronary artery rings compared with untreated control vessels. In addition, HIV gp120 with TNF-alpha pretreatment significantly reduced endothelial nitric oxide synthase (eNOS) expression-both mRNA and protein levels-in porcine coronary artery rings and HCAECs compared with untreated controls. Furthermore, TNF-alpha pretreatment substantially increased intercellular adhesion molecule-1 (ICAM-1) expression in artery rings and HCAECs. Anti-gp120 or anti-ICAM-1 antibody significantly blocked these effects of HIV gp120. Silencing of ICAM-1 by siRNA oligonucleotides significantly blocked the effect of gp120 on eNOS downregulation in TNF-alpha-pretreated HCAECs. HIV gp120 and TNF-alpha synergistically reduce eNOS expression and cause endothelial dysfunction in both porcine coronary arteries and HCAECs. ICAM-1 induced by TNF-alpha pretreatment may mediate HIV gp120-induced endothelial dysfunction, which suggests a novel molecular mechanism of HIV gp120-ICAM-1 interaction inducing endothelial dysfunction.