PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells.
Endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor 1-alpha (HIF-1alpha) are important regulators of endothelial function, which plays a role in the pathophysiology of heart failure (HF). PGE1 analog treatment in patients with HF elicits beneficial hemodynamic effects, but the precise mechanisms have not been investigated. We have investigated the effects of the PGE1 analog alprostadil on eNOS, VEGF, and HIF-1alpha expression in human umbilical vein endothelial cells (HUVEC) using RT-PCR and immunoblotting under normoxic and hypoxic conditions. In addition, we studied protein expression by immunohistochemical staining in explanted hearts from patients with end-stage HF, treated or untreated with systemic alprostadil. Alprostadil causes an upregulation of eNOS and VEGF protein and mRNA expression in HUVEC and decreases HIF-1alpha. Hypoxia potently increased eNOS, VEGF, and HIF-1alpha synthesis. The alprostadil-induced upregulation of eNOS and VEGF was prevented by inhibition of MAPKs with PD-98056 or U-0126. Consistently, the expression of eNOS and VEGF was increased, and HIF-1alpha was reduced in failing hearts treated with alprostadil. The potent effects of alprostadil on endothelial VEGF and eNOS synthesis may be useful for patients with HF where endothelial dysfunction is involved in the disease process.
Haider
Dominik G
DG
Dept. of Angiology, Medical University of Vienna, Austria.
Bucek
Robert A
RA
Giurgea
Aura G
AG
Maurer
Gerald
G
Glogar
Helmut
H
Minar
Erich
E
Wolzt
Michael
M
Mehrabi
Mohammad R
MR
Baghestanian
Mehrdad
M
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D020928:Mitogen-Activated Protein Kinases; D000527:Alprostadil