Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 289; no. 2; pp. H701 - H707
• Main Authors: Turkseven, Saadet, Kruger, Adam, Mingone, Christopher J, Kaminski, Pawel, Inaba, Muneo, Rodella, Luigi F, Ikehara, Susumu, Wolin, Michael S, Abraham, Nader G
• Format: Journal Article
• Language: English
• Published: United States 01.08.2005
• Subjects: Acetylcholine - pharmacology; Animals; Antioxidants - metabolism; Aorta - enzymology; Blood Vessels - drug effects; Blood Vessels - enzymology; Blood Vessels - metabolism; Catalase - metabolism; Cobalt - pharmacology; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - metabolism; Endothelium, Vascular - enzymology; Enzyme Induction; Heme Oxygenase (Decyclizing) - biosynthesis; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Immunohistochemistry; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Protoporphyrins - pharmacology; Rats; Rats, Sprague-Dawley; Superoxide Dismutase - metabolism; Superoxides - metabolism; Vasodilator Agents - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00024.2005

Departments of 1 Pharmacology, 2 Medicine, and 3 Physiology, New York Medical College, Valhalla, New York; 4 Department of Pathology, Kansai Medical University, Osaka, Japan; and 5 Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy Submitted 10 January 2005 ; accepted in final form 17 March 2005 Increased heme oxygenase (HO)-1 activity attenuates endothelial cell apoptosis and decreases superoxide anion (O 2 – ) formation in experimental diabetes by unknown mechanisms. We examined the effect of HO-1 protein and HO activity on extracellular SOD (EC-SOD), catalase, O 2 – , inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) levels and vascular responses to ACh in control and diabetic rats. Vascular EC-SOD and plasma catalase activities were significantly reduced in diabetic compared with nondiabetic rats ( P < 0.05). Upregulation of HO-1 expression by intermittent administration of cobalt protoporphyrin, an inducer of HO-1 protein and activity, resulted in a robust increase in EC-SOD but no significant change in Cu-Zn-SOD. Administration of tin mesoporphyrin, an inhibitor of HO-1 activity, decreased EC-SOD protein. Increased HO-1 activity in diabetic rats was associated with a decrease in iNOS but increases in eNOS and plasma catalase activity. On the other hand, aortic ring segments from diabetic rats exhibited a significant reduction in vascular relaxation to ACh, which was reversed with cobalt protoporphyrin treatment. These data demonstrate that an increase in HO-1 protein and activity, i.e., CO and bilirubin production, in diabetic rats brings about a robust increase in EC-SOD, catalase, and eNOS with a concomitant increase in endothelial relaxation and a decrease in O 2 – . These observations in experimental diabetes suggest that the vascular cytoprotective mechanism of HO-1 against oxidative stress requires an increase in EC-SOD and catalase. antioxidant enzymes; extracellular superoxide dismutase; nitric oxide synthase; endothelial dysfunction; superoxide; oxidative stress Address for reprint requests and other correspondence: N. G. Abraham, Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595 (E-mail: nader_abraham{at}nymc.edu )