PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes.
PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes.
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发表时间：
2004
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通讯作者：
Z. Bagi;A. Koller;G. Kaley
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作者：
Z. Bagi;A. Koller;G. Kaley
我们验证了用罗格列酮（ROSI）短期治疗2型糖尿病（DM）小鼠的假设，罗格列酮（ROSI）是一种过氧化物酶体增殖物激活受体- γ的激动剂，通过一种与高血糖和高胰岛素血症无关的机制，通过减少氧化应激来改善受损的冠状动脉扩张。对照组和2型DM （db/db）小鼠给予ROSI (3 mg x kg（-1) x day(-1)）治疗7 d，对血清葡萄糖和胰岛素浓度无显著影响。与对照组相比，在db/db小鼠的血清中，颈动脉中8-异前列腺素和二氢乙胺可检测的超氧化物的产生水平在ROSI治疗后显著升高，并降低。在db/db小鼠分离的冠状动脉（直径约80微米）中，通过体外给药罗布麻（NAD(P) h -氧化酶抑制剂）或体内ROSI处理，对乙酰胆碱（ACh）、一氧化氮（NO）供体NONOate的扩张减少和流量增加显著增强，然后通过NO合成酶抑制剂N(omega)-硝基- l -精氨酸甲酯显著降低反应。db/db小鼠主动脉SOD和过氧化氢酶活性降低，NAD(P)H氧化酶活性增强。ROSI处理提高了过氧化氢酶活性，降低了NAD(P)H氧化酶活性，但对SOD活性没有影响。这些发现表明，ROSI治疗通过减少血管NAD(P)H氧化酶衍生的超氧化物产生和增强过氧化氢酶活性，增强了NO介导的冠状动脉扩张。因此，除了先前揭示的有益代谢作用外，罗格列酮的抗氧化作用可能保护2型糖尿病患者的冠状动脉功能。
We tested the hypothesis that short-term treatment of mice with Type 2 diabetes mellitus (DM) with rosiglitazone (ROSI), an agonist of peroxisome proliferator-activated receptor-gamma, ameliorates the impaired coronary arteriolar dilation by reducing oxidative stress via a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and Type 2 DM (db/db) mice were treated with ROSI (3 mg x kg(-1) x day(-1)) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared with controls, in db/db mice serum levels of 8-isoprostane and dihydroethydine-detectable superoxide production in carotid arteries were significantly elevated and were reduced by ROSI treatment. In coronary arterioles (diameter, approximately 80 microm) isolated from db/db mice, the reduced dilations to ACh, the nitric oxide (NO) donor NONOate, and increases in flow were significantly augmented either by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase, or by in vivo ROSI treatment, responses that were then significantly reduced by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. In aortas of db/db mice, activity of 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. These findings suggest that ROSI treatment enhances NO mediation of coronary arteriolar dilations due to the reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.