Shida Takuya, Nozawa Takashi, Sobajima Mitsuo, Ihori Hiroyuki, Matsuki Akira, Inoue Hiroshi
Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Heart Vessels. 2014 Jul;29(4):532-41. doi: 10.1007/s00380-013-0402-6. Epub 2013 Aug 25.
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(2α) (PGF(2α)) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-α-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 × 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(2α) levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1α 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.
糖尿病性心肌病与氧化应激增加和血管内皮功能障碍有关，进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能改善链脲佐菌素诱导的糖尿病（DM）中的糖尿病性心肌病并改善冠状动脉微血管系统。将氟伐他汀（10毫克/千克/天）或赋形剂口服给予有或无DM的大鼠12周。通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基p22（phox）和gp91（phox）mRNA表达以及心肌8-异前列腺素F（2α）（PGF（2α））水平评估心肌氧化应激。使用抗CD31和抗α-平滑肌肌动蛋白（SMA）抗体评估心肌血管密度。氟伐他汀不影响血压或血浆胆固醇，但与赋形剂相比，可减轻糖尿病大鼠左心室（LV）最小压力的增加并改善LV收缩功能障碍（LV dP/dt，8.9±1.8对5.4±1.0×10（3）mmHg/s，P<0.05）。糖尿病时心肌氧化应激增加，但氟伐他汀显著降低p22（phox）和gp91（phox）mRNA表达以及心肌PGF（2α）水平。氟伐他汀增强心肌内皮型一氧化氮合酶（eNOS）蛋白水平，并增加eNOS、血管内皮生长因子和缺氧诱导因子-1αmRNA表达。糖尿病大鼠中CD31阳性细胞密度低于非糖尿病大鼠（28.4±13.2对48.6±4.3/视野，P<0.05），氟伐他汀恢复了细胞数量（57.8±18.3/视野），尽管各组间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脏功能、氧化应激或血管密度。这些结果表明，氟伐他汀对糖尿病性心肌病的有益作用可能至少部分是通过降低心肌氧化应激和上调血管生成因子来改善冠状动脉微血管系统而产生的。
