Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes.
Increased heme oxygenase (HO)-1 activity attenuates endothelial cell apoptosis and decreases superoxide anion (O2-) formation in experimental diabetes by unknown mechanisms. We examined the effect of HO-1 protein and HO activity on extracellular SOD (EC-SOD), catalase, O2-, 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 O2-. 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.
Turkseven
Saadet
S
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Kruger
Adam
A
Mingone
Christopher J
CJ
Kaminski
Pawel
P
Inaba
Muneo
M
Rodella
Luigi F
LF
Ikehara
Susumu
S
Wolin
Michael S
MS
Abraham
Nader G
NG
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001011:Aorta / Q000201:enzymology; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D003035:Cobalt / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000201:enzymology; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007150:Immunohistochemistry; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D011524:Protoporphyrins; D014665:Vasodilator Agents; D013481:Superoxides; D003035:Cobalt; C007095:cobaltiprotoporphyrin; D002374:Catalase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D013482:Superoxide Dismutase; C018021:cobaltous chloride; D000109:Acetylcholine