Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats
Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats
复制标题
DOI：
10.1210/en.2006-1355
复制
发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Sowers, James R.
中科院分区：
文献类型：
--
作者：
Habibi, Javad;Whaley-Connell, Adam;Sowers, James R.
已知血管紧张素II（Ang-II）刺激的烟酰胺腺嘌呤二核苷酸磷酸还原（NADPH）氧化酶活性和氧化应激的增加在心脏重塑中起关键作用。异戊二烯化的抑制和小G蛋白（如Rac 1，NADPH氧化酶的一种组分）的活化可能介导3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）的抗氧化作用。在这项研究中，我们研究了瑞舒伐他汀对心脏氧化应激和重塑的影响，在转基因大鼠（Ren 2）过度表达小鼠肾素基因与心脏血管生成素II水平升高。我们用瑞舒伐他汀（10 mg/ kg . d）或媒介物3周。在治疗期结束时，评估左心室质量、室壁厚度、射血分数（通过超声心动图）和心脏重塑（通过光学显微镜和免疫组织化学）。此外，心肌硝基酪氨酸，丙二醛，NADPH氧化酶亚基（gp 91（phox），p40（phox），和p22（phox）），和Rac 1的含量进行了免疫化学分析。Ren 2大鼠的收缩压显著高于SD大鼠（P < 0.05）;瑞舒伐他汀对两组大鼠的收缩压均无显著影响。瑞舒伐他汀可显著改善Ren 2大鼠的心室射血分数、心肌肥厚和血管周围纤维化（P < 0.05），但对SD大鼠无明显影响。此外，瑞舒伐他汀给药显著降低了心肌gp 91（phox）、p40（phox）、p22（phox）和Rac 1表达。这些变化伴随着心肌脂质过氧化（硝基酪氨酸和丙二醛含量）的平行减少（P < 0.05）。这些结果表明，在Ang-II依赖性Ren 2模型中，体内他汀类药物治疗通过其对心脏的直接作用减少氧化应激和重塑，包括心室质量回归。
Angiotensin-II (Ang-II)-stimulated increases in nicotinamide adenine dinucleotide phosphate reduced ( NADPH) oxidase activity and oxidative stress are known to play a key role in cardiac remodeling. Inhibition of isoprenylation and activation of small G proteins, such as Rac1, a component of NADPH oxidase, may mediate the antioxidant actions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). In this study, we investigated the effects of rosuvastatin on cardiac oxidative stress and remodeling in transgenic rats (Ren2) overexpressing the mouse renin gene with elevated cardiac levels of Ang-II. We treated 6- to 7-wk- old Ren2 rats and age-matched Sprague-Dawley (SD) rats with rosuvastatin ( 10 mg/ kg . d) or vehicle for 3 wk. At the end of the treatment period, left ventricular mass, wall thickness, ejection fraction ( by echocardiography), and cardiac remodeling ( by light microscopy and immunohistochemistry) were assessed. In addition, myocardial content of nitrotyrosine, malondialdehyde, NADPH-oxidase subunits (gp91(phox), p40(phox), and p22(phox)), and Rac1 were analyzed by immunochemistry. Systolic blood pressure was significantly higher in Ren2 rats, compared with SD rats ( P < 0.05); rosuvastatin had no significant effect on systolic blood pressure in either group. In Ren2, but not SD rats, rosuvastatin significantly improved the ventricular ejection fraction, cardiac hypertrophy, and perivascular fibrosis ( P < 0.05). In addition, rosuvastatin administration significantly decreased the accentuated myocardial gp91(phox), p40(phox), p22(phox), and Rac1 expression. These changes were accompanied by a parallel reduction in myocardial lipid peroxidation ( nitrotyrosine and malondialdehyde content) ( P < 0.05). These results suggest that in vivo statin treatment through its direct actions on the heart reduces oxidative stress and remodeling including ventricular mass regression in the Ang-II-dependent Ren2 model.