Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity.
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.
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.).
Diansa
D
Gao
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.).
Zhong
Z
Zuo
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.).
Jing
J
Tian
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.).
Quaisar
Q
Ali
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.).
Yi
Y
Lin
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.).
Han
H
Lei
From the Department of Cardiology (D.G., Z.Z., H.L., Z.S.) and Department of Physical Examination (J.T.), the First Affiliated Hospital, Chongqing Medical University, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (D.G., Q.A., Y.L., Z.S.). zhongjie-sun@ouhsc.edu.
Zhongjie
Z
Sun
D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005966:Glucuronidase / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011446:Prospective Studies; D063177:Pulse Wave Analysis; D056564:Sirtuin 1 / Q000235:genetics*; D059289:Vascular Stiffness / Q000235:genetics*
D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D000804:Angiotensin II; D055372:AMP-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
angiotensin II; arteries; blood pressure; elastin; hypertension