Diabetes-induced coronary vascular dysfunction involves increased arginase activity.
Increases in arginase activity have been reported in a variety of disease conditions characterized by vascular dysfunction. Arginase competes with NO synthase for their common substrate arginine, suggesting a cause and effect relationship. We tested this concept by experiments with streptozotocin diabetic rats and high glucose (HG)-treated bovine coronary endothelial cells (BCECs). Our studies showed that diabetes-induced impairment of vasorelaxation to acetylcholine was correlated with increases in reactive oxygen species and arginase activity and arginase I expression in aorta and liver. Treatment of diabetic rats with simvastatin (5 mg/kg per day, subcutaneously) or L-citrulline (50 mg/kg per day, orally) blunted these effects. Acute treatment of diabetic coronary arteries with arginase inhibitors also reversed the impaired vasodilation to acetylcholine. Treatment of BCECs with HG (25 mmol/L, 24 hours) also increased arginase activity. This effect was blocked by treatment with simvastatin (0.1 micromol/L), the Rho kinase inhibitor Y-27632 (10 micromol/L), or L-citrulline (1 mmol/L). Superoxide and active RhoA levels also were elevated in HG-treated BCECs. Furthermore, HG significantly diminished NO production in BCECs. Transfection of BCECs with arginase I small interfering RNA prevented the rise in arginase activity in HG-treated cells and normalized NO production, suggesting a role for arginase I in reduced NO production with HG. These results indicate that increased arginase activity in diabetes contributes to vascular endothelial dysfunction by decreasing L-arginine availability to NO synthase.
Romero
Maritza J
MJ
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.
Platt
Daniel H
DH
Tawfik
Huda E
HE
Labazi
Mohamed
M
El-Remessy
Azza B
AB
Bartoli
Manuela
M
Caldwell
Ruth B
RB
Caldwell
Robert W
RW
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000097:blood / Q000378:metabolism; D001667:Binding, Competitive; D002417:Cattle; D003327:Coronary Disease / Q000201:enzymology* / Q000209:etiology*; D003331:Coronary Vessels / Q000503:physiopathology; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D004730:Endothelium, Vascular / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats
D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D001119:Arginase