title: Platelet-derived growth factor stimulates heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells.
abstract: Recent studies indicate that vascular smooth muscle cells (VSMCs) generate CO from the degradation of heme by the enzyme heme oxygenase-1 (HO-1). Because platelet-derived growth factor (PDGF) modulates various responses of VSMCs, we examined whether this peptide regulates the expression of HO-1 and the production of CO by rat aortic SMCs. Treatment of SMCs with PDGF resulted in a time- and concentration-dependent increase in the levels of HO-1 mRNA and protein. Both actinomycin D and cycloheximide blocked PDGF-stimulated HO-1 mRNA and protein. In addition, PDGF stimulated the production of reactive oxygen species by SMCs. Both the PDGF-mediated generation of reactive oxygen species and the induction of HO-1 protein was inhibited by the antioxidant N-acetyl-L-cysteine. Incubation of platelets with PDGF-treated SMCs resulted in a significant increase in platelet cGMP concentration that was reversed by treatment of SMCs with the HO-1 inhibitor tin protoporphyrin-IX or by addition of the CO scavenger hemoglobin to platelets. In contrast, the nitric oxide inhibitor methyl-L-arginine did not block the stimulatory effect of PDGF-treated SMCs on platelet cGMP. Finally, incubation of SMCs with the releasate from collagen-activated platelets induced HO-1 protein expression that was blocked by a neutralizing antibody to PDGF. These results demonstrate that either administered exogenously or released by platelets, PDGF stimulates HO-1 gene expression and CO synthesis in vascular smooth muscle. The ability of PDGF to induce HO-1-catalyzed CO release by VSMCs may represent a novel mechanism by which this growth factor regulates vascular cell and platelet function.
authors.affiliation: Houston VA Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. wdurante@bcm.tmc.edu
authors.forename: W
authors.initials: W
authors.lastname: Durante
authors.forename: K J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: A I
authors.initials: AI
authors.lastname: Schafer
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats
chemical_list: D010982:Platelet-Derived Growth Factor; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; C027742:delta-N-methylarginine; D002248:Carbon Monoxide; D001120:Arginine; D003513:Cycloheximide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1