Rosuvastatin increases vascular endothelial PPARγ expression and corrects blood pressure variability in obese dyslipidaemic mice
Rosuvastatin increases vascular endothelial PPARγ expression and corrects blood pressure variability in obese dyslipidaemic mice
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DOI：
10.1093/eurheartj/ehm540
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发表时间：
2008-01-01
影响因子：
39.3
通讯作者：
Balligand, Jean-Luc
中科院分区：
文献类型：
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作者：
Desjardins, Fanny;Sekkali, Belaid;Balligand, Jean-Luc
目的他汀类药物通过降胆固醇作用改善动脉粥样硬化性疾病。在代谢综合征中，后者是否专门介导类似的益处，例如对高血压的益处尚不清楚。我们研究了瑞舒伐他汀对这种综合征的成分的影响，在小鼠中复制的LDL受体和瘦素（DKO）的双重缺陷。方法和结果DKO接受瑞舒伐他汀（10毫克/公斤/天或20毫克/公斤/天）或生理盐水12周。盐水处理的DKO小鼠血压（BP）升高，遥测记录了一氧化氮敏感的BP变异性。与生理盐水相比，瑞舒伐他汀（20 mg/kg/天）对体重增加无影响，对血浆胆固醇有轻微影响。尽管胰岛素敏感性未完全纠正，瑞舒伐他汀完全纠正了血压及其变异性（P = 0.01），同时上调了主动脉弓中的PPAR γ（但非PPAR α）。瑞舒伐他汀同样增加了离体内皮细胞中的PPAR γ（P = 0.002）和SOD 1（P = 0.01）表达。这两个GW 9662，一个过氧化物酶体增殖物激活受体γ-特异性拮抗剂，和siRNA提出对过氧化物酶体增殖物激活受体γ废除瑞舒伐他汀的效果，这是复制在过氧化物酶体增殖物激活受体γ-（但不是过氧化物酶体增殖物激活受体α-）依赖transactivation assessment.Conclusion除了部分改善胰岛素敏感性，瑞舒伐他汀正常化的肥胖血脂异常小鼠的血压稳态，独立于体重或血浆胆固醇的变化。内皮细胞中的过氧化物酶体增殖物激活受体γ和超氧化物歧化酶1的上调可能是他汀类药物治疗的独特血管保护作用。
Aims Statins improve atherosclerotic diseases through cholesterol-reducing effects. Whether the latter exclusively mediate similar benefits, e.g. on hypertension, in the metabolic syndrome is unclear. We examined the effects of rosuvastatin on the components of this syndrome, as reproduced in mice doubly deficient in LDL receptors and leptin (DKO).Methods and results DKO received rosuvastatin (10 mg/kg/day or 20 mg/kg/day) or saline for 12 weeks. Saline-treated DKO mice had elevated blood pressure (BP) and nitric oxide-sensitive BP variability recorded by telemetry. Compared with saline, rosuvastatin (20 mg/kg/day) had no effect on weight gain and a minor effect on plasma cholesterol. Despite incomplete correction of insulin sensitivity, rosuvastatin fully corrected BP and its variability (P = 0.01), in conjunction with upregulation of PPAR gamma (but not PPAR alpha) in the aortic arch. Rosuvastatin similarly increased PPAR gamma (P = 0.002) and SOD1 (P = 0.01) expression in isolated endothelial cells. Both GW9662, a PPAR gamma-specific antagonist, and siRNA raised against PPAR gamma abrogated rosuvastatin's effect, which was reproduced in PPAR gamma- (but not PPAR alpha-) dependent transactivation assays.Conclusion Beyond partial improvement in insulin sensitivity, rosuvastatin normalized BP homeostasis in obese dyslipidaemic mice independently of changes in body weight or plasma cholesterol. Upregulation of PPAR gamma and SOD1 in the endothelium may be involved as a unique vasculoprotective effect of statin treatment.