Abstract 13959: SIRT1 Deacetylase Mediates Klotho Gene Deficiency-induced Arterial Remodeling and Stiffness
Objective: Arterial stiffness is an independent risk factor for stroke and myocardial infarction. This study was designed to investigate the potential 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.
Methods and Results: 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.
Conclusion: This study provides the first evidence that Klotho deficiency downregulates SIRT1 activity in arterial endothelial and smooth muscle cells contributing to the pathogenesis of arterial remodeling and stiffening. Pharmacological activation of SIRT1 is likely to be an effective therapeutic approach for arterial stiffness and hypertension.
Author Disclosures: D. Gao: None. Z. Zuo: None. J. Tian: None. Q. Ali: None. Y. Lin: None. H. Lei: None. Z. Sun: None.
- © 2016 by American Heart Association, Inc.