Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways
Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways
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DOI：
10.1042/cs20140456
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发表时间：
2015-04-01
期刊：
影响因子：
6
通讯作者：
Touyz, Rhian M.
中科院分区：
文献类型：
--
作者：
Bruder-Nascimento, Thiago;Callera, Glaucia E.;Touyz, Rhian M.
氧化应激[活性氧（ROS）的生物利用度增加]在内皮功能障碍和血管炎症中起作用，这是糖尿病血管损伤的基础。他汀类药物是一种降胆固醇药物，通过未知的机制对糖尿病具有血管保护作用。我们检验了阿托伐他汀降低NADPH氧化酶（Nox）衍生的ROS生成和糖尿病相关血管损伤的假设。给予Lepr（db）/Lepr（db）（db/db）小鼠、2型糖尿病模型和对照Lepr（db）/Lepr（+）（db/+）小鼠阿托伐他汀（10 mg/kg/天，2周）。阿托伐他汀改善db/db小鼠的葡萄糖耐量。阿托伐他汀可抑制db/db小鼠的全身和血管氧化应激，其特征分别为血浆TBARS（硫代巴比妥酸反应物质）水平升高和血管Nox源性ROS生成增加。与db/+小鼠相比，db/db小鼠血管中Nox调节亚基p47（phox）和小GTdR Rac 1/2的胞浆-膜易位增加，阿托伐他汀减弱了这种作用。在db/db小鼠中，血管Nox 1/2/4表达的增加和氧化还原敏感性丝裂原活化蛋白激酶（MAPK）磷酸化的增加被阿托伐他汀消除。阿托伐他汀可减弱db/db小鼠动脉中的促炎信号传导（I κ B-α降低，NF-κ B p50表达增加，NF-κ B p65磷酸化增加）和相关血管炎症[血管细胞粘附分子-1（VCAM-1）表达和血管单核细胞粘附]。阿托伐他汀使db/db小鼠乙酰胆碱（Ach）和胰岛素（INS）诱导的血管舒张受损恢复正常。我们的研究结果表明，在糖尿病小鼠中，阿托伐他汀通过降低Rac 1/2和Nox的激活来降低血管氧化应激和炎症，并改善血管损伤。这些发现阐明了他汀类药物保护糖尿病血管损伤的氧化还原敏感性和Rac 1/2依赖性机制。
Oxidative stress [increased bioavailability of reactive oxygen species (ROS)] plays a role in the endothelial dysfunction and vascular inflammation, which underlie vascular damage in diabetes. Statins are cholesterol-lowering drugs that are vasoprotective in diabetes through unknown mechanisms. We tested the hypothesis that atorvastatin decreases NADPH oxidase (Nox)-derived ROS generation and associated vascular injury in diabetes. Lepr(db)/Lepr(db) (db/db) mice, a model of Type 2 diabetes and control Lepr(db)/Lepr(+) (db/+) mice were administered atorvastatin (10 mg/kg per day, 2 weeks). Atorvastatin improved glucose tolerance in db/db mice. Systemic and vascular oxidative stress in db/db mice, characterized by increased plasma TBARS (thiobarbituric acid-reactive substances) levels and exaggerated vascular Nox-derived ROS generation respectively, were inhibited by atorvastatin. Cytosol-to-membrane translocation of the Nox regulatory subunit p47(phox) and the small GTPase Rac1/2 was increased in vessels from db/db mice compared with db/+ mice, an effect blunted by atorvastatin. The increase in vascular Nox1/2/4 expression and increased phosphorylation of redox-sensitive mitogen-activated protein kinases (MAPKs) was abrogated by atorvastatin in db/db mice. Pro-inflammatory signalling (decreased I kappa B-alpha and increased NF-kappa B p50 expression, increased NF-kappa B p65 phosphorylation) and associated vascular inflammation [vascular cell adhesion molecule-1 (VCAM-1) expression and vascular monocyte adhesion], which were increased in aortas of db/db mice, were blunted by atorvastatin. Impaired acetylcholine (Ach)- and insulin (INS)-induced vasorelaxation in db/db mice was normalized by atorvastatin. Our results demonstrate that, in diabetic mice, atorvastatin decreases vascular oxidative stress and inflammation and ameliorates vascular injury through processes involving decreased activation of Rac1/2 and Nox. These findings elucidate redox-sensitive and Rac1/2-dependent mechanisms whereby statins protect against vascular injury in diabetes.