Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity.
Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity.
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DOI：
10.1161/hypertensionaha.116.07709
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Sun Z
中科院分区：
文献类型：
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作者：
Gao D;Zuo Z;Tian J;Ali Q;Lin Y;Lei H;Sun Z
动脉硬化是中风和心肌梗死的独立危险因素。本研究旨在探讨SIRT1（一种重要的去乙酰化酶）在动脉僵硬和高血压发病机制中的作用及其与Klotho（一种肾源性衰老抑制蛋白）的关系。我们发现，在动脉僵硬和高血压患者中，Klotho的血清水平下降了近45%。有趣的是，Klotho单倍体缺陷引起动脉硬化和高血压，Klotho单倍体缺陷（KL+/−）小鼠的脉搏波速度（PWV）和血压（BP）显著增加。值得注意的是，KL+/−小鼠的主动脉内皮细胞和平滑肌细胞中SIRT1的表达和活性显著降低，表明Klotho缺陷下调了SIRT1。SRT1720 （15 mg/kg/天，IP）是一种特异性SIRT1激活剂，治疗后Klotho缺陷引起的KL+/−小鼠动脉僵硬和高血压消失。Klotho缺乏与主动脉中amp活化蛋白激酶α (AMPKα)和内皮型一氧化氮合酶（eNOS）活性显著降低有关，SRT1720可消除这些活性。此外，Klotho缺乏上调了NADPH氧化酶活性和超氧化物的产生，增加了胶原表达，并增强了主动脉介质中弹性蛋白的断裂。这些Klotho缺陷相关的变化被SRT1720阻断。总之，本研究首次提供了Klotho缺乏症下调动脉内皮细胞和平滑肌细胞SIRT1活性的证据。SIRT1的药理激活可能是动脉僵硬和高血压的有效治疗策略。
Arterial stiffness is an independent risk factor for stroke and myocardial infarction. This study was designed to investigate the role of SIRT1, an important deacetylase, and its relationship with Klotho, a kidney-derived aging-suppressor protein, in the pathogenesis of arterial stiffness and hypertension. We found that the serum level of Klotho was decreased by nearly 45% in patients with arterial stiffness and hypertension. Interestingly, Klotho haplodeficiency caused arterial stiffening and hypertension, as evidenced by significant increases in pulse wave velocity (PWV) and blood pressure (BP) in Klotho-haplodeficient (KL+/−) mice. Notably, the expression and activity of SIRT1 were decreased significantly in aortic endothelial and smooth muscle cells in KL+/− mice, suggesting that Klotho deficiency downregulates SIRT1. Treatment with SRT1720 (15 mg/kg/day, IP), a specific SIRT1 activator, abolished Klotho deficiency-induced arterial stiffness and hypertension in KL+/− mice. Klotho deficiency was associated with significant decreases in activities of AMP-activated protein kinase alpha (AMPKα) and endothelial nitric oxide synthase (eNOS) in aortas, which were abolished by SRT1720. Furthermore, Klotho deficiency upregulated NADPH oxidase activity and superoxide production, increased collagen expression, and enhanced elastin fragmentation in the media of aortas. These Klotho deficiency-associated changes were blocked by SRT1720. In conclusion, this study provides the first evidence that Klotho deficiency downregulates SIRT1 activity in arterial endothelial and smooth muscle cells. Pharmacological activation of SIRT1 may be an effective therapeutic strategy for arterial stiffness and hypertension.