Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature
Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature
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DOI：
10.1007/s00380-013-0402-6
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发表时间：
2014-07-01
影响因子：
1.5
通讯作者：
Inoue, Hiroshi
中科院分区：
文献类型：
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作者：
Shida, Takuya;Nozawa, Takashi;Inoue, Hiroshi
糖尿病心肌病与氧化应激增加和血管内皮功能障碍有关，从而导致冠状动脉微血管病变。我们测试了他汀类药物诱导的氧化还原失衡改善是否可以改善链脲佐菌素诱导的糖尿病(DM)患者的糖尿病心肌病变和冠状动脉微血管。用氟伐他汀(10 mg/kg/d)或赋形剂对糖尿病大鼠和非糖尿病大鼠灌胃12周。用NADPH(烟酰胺腺嘌呤二核苷酸磷酸)氧化酶亚单位p22(Phox)和gp91(Phox)mRNA表达和8-异前列腺素F-2α(PGF(2α))水平评价心肌氧化应激。用抗CD31和抗α-平滑肌肌动蛋白(SMA)抗体检测心肌血管密度。氟伐他汀对糖尿病大鼠血压和血浆胆固醇无明显影响，但可减轻DM大鼠左室最小压力的升高，改善左心室收缩功能障碍(LVdp/dt，8.9+/-1.8vs5.4+/-1.0×10(3)mm Hg/S，P<；0.05)。糖尿病大鼠心肌氧化应激增加，但氟伐他汀显著降低心肌组织中p22(Phox)和gp91(Phox)的mRNA表达和PGF(2α)水平。氟伐他汀可增加心肌内皮型一氧化氮合酶(ENOS)蛋白水平，增加eNOS、血管内皮生长因子和低氧诱导因子-1α的mRNA表达。糖尿病大鼠CD31阳性细胞密度低于非糖尿病大鼠(28.4+/-13.2vs48.6+/-4.3个/视野，P<；0.05)，氟伐他汀可恢复CD31阳性细胞密度(57.8+/-18.3个/视野)，但两组间SMA阳性细胞密度无显著差异。氟伐他汀不影响非糖尿病大鼠的心功能、氧化应激或血管密度。这些结果表明，氟伐他汀对糖尿病心肌病的有益作用可能至少部分是通过减少心肌氧化应激和上调血管生成因子来改善冠脉微血管。
Diabetic cardiomyopathy is associated with increased oxidative stress and vascular endothelial dysfunction, which lead to coronary microangiopathy. We tested whether statin-induced redox imbalance improvements could ameliorate diabetic cardiomyopathy and improve coronary microvasculature in streptozotocin-induced diabetes mellitus (DM). Fluvastatin (10 mg/kg/day) or vehicle was orally administered for 12 weeks to rats with or without DM. Myocardial oxidative stress was assessed by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase subunit p22(phox) and gp91(phox) mRNA expression, and myocardial 8-iso-prostaglandin F-2 alpha (PGF(2 alpha)) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-alpha-smooth muscle actin (SMA) antibodies. Fluvastatin did not affect blood pressure or plasma cholesterol, but attenuated increased left ventricular (LV) minimum pressure and ameliorated LV systolic dysfunction in DM rats in comparison with vehicle (LV dP/dt, 8.9 +/- 1.8 vs 5.4 +/- 1.0 x 10(3) mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22(phox) and gp91(phox) mRNA expression and myocardial PGF(2 alpha) levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1 alpha mRNA expression. CD31-positive cell densities were lower in DM rats than in non-DM rats (28.4 +/- 13.2 vs 48.6 +/- 4.3/field, P < 0.05) and fluvastatin restored the number (57.8 +/- 18.3/field), although there were no significant differences in SMA-positive cell densities between groups. Fluvastatin did not affect cardiac function, oxidative stress, or vessel densities in non-DM rats. These results suggest that beneficial effects of fluvastatin on diabetic cardiomyopathy might result, at least in part, from improving coronary microvasculature through reduction in myocardial oxidative stress and upregulation of angiogenic factor.