Abstract 1690: Does Elevated Arginase Activity Contribute To Diabetes-Induced Endothelial Dysfunction?
L-Arginine (L-arg) is not only the substrate for nitric oxide synthase (NOS) to produce NO, but also for arginase, which catalyzes conversion L-arg to ornithine and urea. In diabetes, increased arginase activity has been suggested to contribute to endothelial dysfunction by decreasing L-arg availability to NOS. We investigated arginase function in rats rendered diabetic with streptozotocin and in bovine aortic endothelial cells (BAEC) treated with peroxynitrite (ONOO−) or high glucose (HG). Our rat studies have shown that 4 weeks of diabetes reduced plasma levels of NO, increased lipid peroxidation and impaired coronary and aortic vasorelaxation to acetylcholine (Ach) that are correlated with increases in arginase activity in both aorta and liver (87% and 233% above control levels, respectively). Concurrent treatment of diabetic rats with simvastatin (5 mg/kg/day, s.c.) or ONOO− scavenger (FeTPPs, 15 mg/kg/day) for 4 wks blunted these effects. Acute treatment of isolated diabetic coronary arteries with the arginase inhibitor L-norvaline (20 mM) also partially reversed the impaired vasodilation to Ach. To determine the impact of oxidative stress on arginase activity, BAEC were exposed to ONOO− (25 μM) or HG(25 mM), both known to increase during diabetes. These treatments resulted in a time dependent increase in arginase activity with peak effects to ONOO− (110% above control) and HG (65% above control) occuring at 6 hr and 48 hr, resectively. These effects were also blocked by pretreatment with simvastatin (10−7M) or the Rho kinase inhibitor Y27632 (10−5 M). Our results suggest that increased arginase activity in diabetes contributes to reduced L-Arg availability for NOS and vascular EC dysfunction. Elevated arginase activity in ECs exposed to peroxynitrite and high glucose suggests that oxidative stress has a key role in this pathological process. Statin treatment is known to enhanced NOS expression and activity, but statins also can reduce arginase activity, enhance L-arg availability and improve NOS function.