title: Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.
abstract: Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-1 activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-1 gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.
authors: Division of Cardiology, Innsbruck University, Innsbruck, Austria. jdulak@mol.uj.edu.pl
authors: Jozef
authors: J
authors: Dulak
authors: Alicja
authors: A
authors: Józkowicz
authors: Roberta
authors: R
authors: Foresti
authors: Aneta
authors: A
authors: Kasza
authors: Matthias
authors: M
authors: Frick
authors: Ihor
authors: I
authors: Huk
authors: Colin J
authors: CJ
authors: Green
authors: Otmar
authors: O
authors: Pachinger
authors: Franz
authors: F
authors: Weidinger
authors: Roberto
authors: R
authors: Motterlini
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D001664:Biliverdine / Q000378:metabolism; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics*; D008665:Metalloporphyrins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008222:Lymphokines; D008665:Metalloporphyrins; D011524:Protoporphyrins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D006427:Hemin; C032628:tin protoporphyrin IX; D007501:Iron; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D003676:Deferoxamine; D001664:Biliverdine; D001663:Bilirubin; D019331:NG-Nitroarginine Methyl Ester