Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1.
Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades heme to carbon monoxide, iron ions, and biliverdin. Its expression can be induced by 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), a natural ligand of peroxisome proliferator-activated receptor-gamma transcription factor. In macrophages and vascular smooth muscle cells, 15d-PGJ(2) up-regulates the expression of vascular endothelial growth factor (VEGF), a fundamental regulator of angiogenesis. Here we investigated the involvement of HO-1 in the 15d-PGJ(2)-mediated regulation of VEGF production by human microvascular endothelial cells (HMEC-1). Resting HMEC-1 released approximately 20 pg/ml VEGF protein after 24 h of incubation. Treatment of cells with 15d-PGJ(2) (1-10 microM) significantly and dose-dependently increased the VEGF promoter activity, mRNA expression, and protein secretion. In the same cells, 15d-PGJ(2) potently induced the expression of HO-1 protein that correlated with HO-1 promoter activity. Activation of HO-1 with hemin or ectopic overexpression of HO-1 in HMEC-1 perfectly mimicked the effect of 15d-PGJ(2) and led to increased VEGF production. Importantly, the inhibition of the HO-1 pathway by tin protoporphyrin-IX significantly reduced the stimulatory effect of 15d-PGJ(2) on VEGF synthesis. Thus, we postulate that the up-regulation of VEGF expression in response to 15d-PGJ(2 )in HMEC-1 is mediated by the activation of HO-1.
Jozkowicz
Alicja
A
Department of Vascular Surgery, AKH, University of Vienna, Austria. alicia.jozkowicz@akh-wien.ac.at
Huk
Ihor
I
Nigisch
Anneliese
A
Weigel
Günter
G
Weidinger
Franz
F
Dulak
Jozef
J
D000818:Animals; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011524:Protoporphyrins / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008222:Lymphokines; D008565:Membrane Proteins; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C037112:9-deoxy-delta-9-prostaglandin D2; D006427:Hemin; C028025:protoporphyrin IX; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D015230:Prostaglandin D2