title: Bone morphogenic protein-4-induced oxidant signaling via protein carbonylation for endothelial dysfunction.
abstract: The increased expression of bone morphogenic protein-4 (BMP-4) under hyperglycemic and diabetic conditions mediates the overgeneration of reactive oxygen species to cause endothelial cell dysfunction and apoptosis. Protein carbonylation plays an important role in oxidant signaling through ligand-receptor interactions in vascular smooth muscle cells, cardiac cells, and bronchial smooth muscle cells to trigger different diseases. However, the role of oxidant signaling via protein carbonylation in endothelial dysfunction is unclear. The level of protein carbonylation was higher in renal arteries from diabetic patients than those from nondiabetic subjects. BMP-4 promoted protein carbonylation, which was followed by decarbonylation or degradation in primary rat aortic endothelial cells. Organ culture of normal C57BL/6J mouse aortas treated with either hydralazine or deferoxamine inhibited the effect of BMP-4 on impairment of acetylcholine-induced endothelium-dependent relaxation (EDR). In isolated diabetic db/db mouse aortas, treatment with hydralazine improved the impaired EDR while deferoxamine had no effect. BMP-4-induced carbonylated proteins in aortic endothelial cells were successfully identified by a proteomic approach. These proteins have important cellular functions and include glyceraldehyde-3-phosphate dehydrogenase, triosephosphate isomerase, alpha-enolase, protein disulfide-isomerase A3, annexin II, 26S protease regulatory subunit, integrin-linked protein kinase, and vimentin. Protein carbonylation induced by BMP-4 was inhibited by BMP-4 antagonist while protein decarbonylation induced by BMP-4 was thiol dependent. The carbonyl signals did not involve 4-hydrononenal and malondialdehyde. The present results suggest that BMP-4- or diabetes-mediated endothelial dysfunction is partly triggered through protein carbonylation and blockade of this metal-catalyzed protein oxidation can be considered as an alternative therapeutic strategy to alleviate diabetic vasculopathy.
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China. Electronic address: henrywong1999@gmail.com.
authors.forename: Chi Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China. Electronic address: yu-huang@cuhk.edu.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000473:pathology; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006830:Hydralazine / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D006830:Hydralazine; D003676:Deferoxamine; D000109:Acetylcholine
keywords: BMP-4; Diabetes mellitus; Endothelial dysfunction; Oxidant signaling; Protein carbonylation