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Activation of SIRT1 Attenuates Klotho Deficiency‐induced Arterial Stiffness and Hypertension via Enhancing AMPKα and eNOS activity
Author(s) -
Gao Diansa,
Zuo Zhong,
Ali Quaisar,
Tian Jing,
Lei Han,
Lin Yi,
Sun Zhongjie
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1206.2
Subject(s) - klotho , medicine , endocrinology , arterial stiffness , downregulation and upregulation , nitric oxide , nadph oxidase , ampk , enos , chemistry , blood pressure , nitric oxide synthase , kinase , protein kinase a , oxidative stress , biochemistry , kidney , gene
Objective Haplodeficiency of klotho causes arterial stiffness and hypertension. W found that Klotho, an aging‐suppressor protein, was significantly decreased in serum of patients with arterial stiffness and hypertension. Deficiency of klotho induces arterial stiffness and hypertension. This study was designed to investigate the underlying mechanism. Methods & Results Klotho mutant heterozygous (+/−) mice and wild‐type (WT) mice were used. Notably, expression and activity of SIRT1, an important deacetylase, were significantly decreased in aortas of KL (+/−) mice which coincided with elevated pulse wave velocity (PWV) and blood pressure (BP). Treatment with SRT1720 (15mg/kg per day IP), a specific SIRT1 activator, abolished klotho deficiency‐induced arterial stiffness and hypertension in KL (+/−) mice. Interestingly, Klotho deficiency was associated with decreases in the activity of AMP‐activated protein kinase (AMPKa) and endothelial nitric oxide synthase (eNOS) in aortas which can be abolished by SRT1720. Furthermore, klotho deficiency upregulated NADPH oxidase activity and superoxide production, increased collagen expression, and decreased elastin expression in the media of aortas. These klotho deficiency‐related changes were blocked by SRT1720. Conclusion This study provided the first evidence that Klotho deficiency‐induced arterial stiffness and hypertension via downregulation of SIRT1. Pharmacological activation of SIRT1 may be an effective therapeutic approach for arterial stiffness and hypertension. Support or Funding Information Supported by NIH R01 HL118558, DK093403, HL105302, and HL102074.