Activation of SIRT1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity

Diansa Gao, Zhong Zuo, Jing Tian, Quaisar Ali, Yi Lin, Han Lei, Zhongjie Sun

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 ≈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 and blood pressure 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/d, 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 α (AMPKα) and endothelial NO 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.

Original languageEnglish (US)
Pages (from-to)1191-1199
Number of pages9
JournalHypertension
Volume68
Issue number5
DOIs
StatePublished - Nov 1 2016

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Vascular Stiffness
AMP-Activated Protein Kinases
Hypertension
Smooth Muscle Myocytes
Aorta
Down-Regulation
Pulse Wave Analysis
Elastin
NADPH Oxidase
Nitric Oxide Synthase
Superoxides
Collagen
Stroke
Myocardial Infarction
Pharmacology
Blood Pressure
Kidney
Therapeutics
Serum
SRT1720

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Activation of SIRT1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity. / Gao, Diansa; Zuo, Zhong; Tian, Jing; Ali, Quaisar; Lin, Yi; Lei, Han; Sun, Zhongjie.

In: Hypertension, Vol. 68, No. 5, 01.11.2016, p. 1191-1199.

Research output: Contribution to journalArticle

Gao, Diansa ; Zuo, Zhong ; Tian, Jing ; Ali, Quaisar ; Lin, Yi ; Lei, Han ; Sun, Zhongjie. / Activation of SIRT1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity. In: Hypertension. 2016 ; Vol. 68, No. 5. pp. 1191-1199.
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