HIV gp120 induces endothelial dysfunction in tumour necrosis factor-alpha-activated porcine and human endothelial cells.
OBJECTIVE
The aim of this study was to determine direct effects and potential molecular mechanisms of HIV gp120, a viral envelope glycoprotein, on endothelial function.


RESULTS
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.


CONCLUSIONS
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.
Jiang
Jun
J
Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Fu
Weiping
W
Wang
Xinwen
X
Lin
Peter H
PH
Yao
Qizhi
Q
Chen
Changyi
C
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D015699:HIV Envelope Protein gp120; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D018799:Intercellular Adhesion Molecule-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin