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Activation Increases NO Bioavailability in Coronary Arterioles in Type 2 Diabetes by Reducing Oxidative Stress
1 Department of Physiology, New York Medical College, Valhalla, New York, USA
* To whom correspondence should be addressed. E-mail: gabor_kaley{at}nymc.edu.
Agonists of peroxisome proliferator-activated receptor gamma{PPAR
) are used to treat metabolic disorders associated with type 2 diabetes mellitus (DM), yet the mechanisms underlying their protective effect on vascular function has not yet been elucidated. We tested the hypothesis that short-term treatment of mice with type 2 DM with rosiglitazone (ROSI), an agonist of PPAR, restores the NO-mediation of dilations in coronary arterioles by reducing oxidative stress, via a mechanism that is unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and type 2 DM (db/db) mice were treated with ROSI (3 mg/kg/day) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared to controls, in db/db mice serum levels of 8-isoprostane (a marker of lipid peroxidation) were significantly elevated (184±24 vs. 247±32 pg/mL), but were significantly reduced by ROSI. In carotid arteries of db/db mice, enhanced superoxide production was detected by dihydroethydine staining, which was reduced by ROSI treatment. In coronary arterioles (diameter: ~80 µm) isolated from db/db mice dilations to flow were reduced, which were restored by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase. In db/db mice the reduced dilations to ACh and the NO donor NONOate, and to increases in flow were significantly augmented by ROSI treatment (to ACh 10-7 mol/L: 28±8 vs. 54±8; to NONOate: 20±3 vs. 46±7; to max flow: 5±3 vs. 23±4 %). The enhanced dilations to ACh and flow were significantly reduced by L-NAME. In aortas of db/db mice, activity of superoxide dismutase (SOD) and catalase was reduced, whereas NAD(P)H-oxidase activity was enhanced. ROSI treatment enhanced catalase and reduced NAD(P)H-oxidase activity, but did not affect the activity of SOD. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in type 2 DM.
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