Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

Abstract

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.

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

“…Compound H rescued aging‐associated downregulation of SIRT1 expression in aortas likely by increasing the circulating SKL levels. Haplodeficiency of Klotho gene led to downregulation of vascular SIRT1 (Gao et al., 2016). Pharmacological activation of SIRT1 attenuated Klotho deficiency‐induced arterial stiffening (Gao et al., 2016).…”

“…Haplodeficiency of Klotho gene led to downregulation of vascular SIRT1 (Gao et al., 2016). Pharmacological activation of SIRT1 attenuated Klotho deficiency‐induced arterial stiffening (Gao et al., 2016). Therefore, downregulation of SIRT1 activity may be an important factor contributing to aging‐induced arterial remodeling and stiffness.…”

“…The histological and IHC analysis was performed as described in our recent studies (Chen, Lin & Sun, 2016; Gao et al., 2016; Lin, Chen & Sun, 2016; Lin & Sun, 2015a,b; Varshney, Ali, Wu & Sun, 2016). For details, see Data S1.…”

Mechanisms and Subclinical Consequences of Aortic Stiffness

“…Klotho -deficient mice also demonstrated reduced expression of SIRT-1 21 that was associated with antioxidant, antiinflammatory 26 and antisenescent 27 phenotypes and downregulation of eNOS. 28 Because Klotho deficiency downregulated aortic SIRT-1 of the mice and activation of SIRT1 by SRT1720 did not alter circulating Klotho concentrations, this suggests that Klotho signaling is upstream from SIRT1 and acts a hormone given that Klotho gene is expressed in the kidney and brain and not aorta.…”

“…18 In contrast, overexpression of Klotho reverses many of the age-related impairments in physiological function and extends lifespan in mice. 19 Klotho gene also results in a secreted protein whereby circulating concentrations are reduced with aging 20 and hypertension 21 , and inversely associated with carotid artery stiffness in humans. 22 Therefore, several recent studies investigated whether reduction in Klotho could be a putative mechanism mediating aortic stiffness with aging.…”