Up-regulation of heme oxygenase provides vascular protection in an animal model of diabetes through its antioxidant and antiapoptotic effects.
Heme oxygenase (HO) plays a critical role in the regulation of cellular oxidative stress. The effects of the reactive oxygen species scavenger ebselen and the HO inducers cobalt protoporphyrin and stannous chloride (SnCl(2)) on HO protein levels and activity, indices of oxidative stress, and the progression of diabetes were examined in the Zucker rat model of type 2 diabetes. The onset of diabetes coincided with an increase in HO-1 protein levels and a paradoxical decrease in HO activity, which was restored by administration of ebselen. Up-regulation of HO-1 expressed in the early development of diabetes produced a decrease in oxidative/nitrosative stress as manifested by decreased levels of 3-nitrotyrosine, superoxide, and cellular heme content. This was accompanied by a decrease in endothelial cell sloughing and reduced blood pressure. Increased HO activity was also associated with a significant increase in the antiapoptotic signaling molecules Bcl-xl and phosphorylation of p38-mitogen-activated protein kinase but no significant increases in Bcl-2 or BAD proteins. In conclusion, 3-nitrotyrosine, cellular heme, and superoxide, promoters of vascular damage, are reduced by HO-1 induction, thereby preserving vascular integrity and protecting cardiac function involving an increase in antiapoptotic proteins.
Kruger
Adam L
AL
Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.
Peterson
Stephen J
SJ
Schwartzman
Michal L
ML
Fusco
Heidi
H
McClung
John A
JA
Weiss
Melvin
M
Shenouda
Sylvia
S
Goodman
Alvin I
AI
Goligorsky
Michael S
MS
Kappas
Attallah
A
Abraham
Nader G
NG
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D003925:Diabetic Angiopathies / Q000150:complications / Q000517:prevention & control*; D042783:Endothelial Cells / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000502:physiology*; D006973:Hypertension / Q000209:etiology / Q000517:prevention & control; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000502:physiology; D030421:Peroxynitrous Acid / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D051020:bcl-X Protein / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D051020:bcl-X Protein; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D006419:Heme Oxygenase (Decyclizing); D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen