title: Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase.
abstract: Klotho was originally discovered as an aging-suppressor gene. The objective of this study is to investigate whether klotho gene deficiency affects high-fat diet (HFD)-induced arterial stiffening. Heterozygous Klotho-deficient (KL(+/-)) mice and WT littermates were fed on HFD or normal diet. HFD increased pulse wave velocity within 5 weeks in KL(+/-) mice but not in wild-type mice, indicating that klotho deficiency accelerates and exacerbates HFD-induced arterial stiffening. A greater increase in blood pressure was found in KL(+/-) mice fed on HFD. Protein expressions of phosphorylated AMP-activated protein kinase-α (AMPKα), phosphorylated endothelial nitric oxide synthase (eNOS), and manganese-dependent superoxide dismutase (Mn-SOD) were decreased, whereas protein expressions of collagen I, transforming growth factor-β1, and Runx2 were increased in aortas of KL(+/-) mice fed on HFD. Interestingly, daily injections of an AMPKα activator, 5-aminoimidazole-4-carboxamide-3-ribonucleoside, abolished the increases in pulse wave velocity, blood pressure, and blood glucose in KL(+/-) mice fed on HFD. Treatment with 5-aminoimidazole-4-carboxamide-3-ribonucleoside for 2 weeks not only abolished the downregulation of phosphorylated AMPKα, phosphorylated eNOS, and Mn-SOD levels but also attenuated the increased levels of collagen I, transforming growth factor-β1, Runx2, superoxide, elastic lamellae breaks, and calcification in aortas of KL(+/-) mice fed on HFD. In cultured mouse aortic smooth muscle cells, cholesterol plus KL-deficient serum decreased phosphorylation levels of AMPKα and LKB1 (an important upstream regulator of AMPKα activity) but increased collagen I synthesis, which can be eliminated by activation of AMPKα by 5-aminoimidazole-4-carboxamide-3-ribonucleoside. In conclusions, Klotho deficiency promoted HFD-induced arterial stiffening and hypertension via downregulation of AMPKα activity.
authors.affiliation: From the Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: From the Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center.
authors.forename: Jianglei
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center. Zhongjie-Sun@ouhsc.edu.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics*; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D059289:Vascular Stiffness / Q000235:genetics*
chemical_list: D055372:AMP-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: AMP-activated protein kinases; cholesterol; collagen; diet, high-fat; elastin; metabolic syndrome X; vascular stiffness