Activation of AMP‐activated protein kinase attenuates arterial stiffening and hypertension in klotho‐deficient mice (867.1)

Abstract

Background: Arterial stiffening is a progressive aging‐related disorder. Klotho is an anti‐aging protein but its role in regulation of arterial stiffening is unknown.Methods and Results: Heterozygous Klotho deficiency (KL+/‐) mice and WT littermate mice were fed on high fat diet (HFD) or normal diet (ND). Pulse wave velocity (PWV), an index of arterial stiffening, was increased in KL+/‐ mice fed on HFD for 5 weeks. Systolic blood pressure and blood glucose levels increased earlier with greater magnitudes in KL+/‐ mice fed on HFD. Notably, protein expression of collagen I, Runx2, and TGFβ1 were increased but protein expression of phosphorylated AMPKα (pAMPKα), phosphorylated eNOS (peNOS), and Mn‐SOD were decreased in aortas of KL+/‐ mice fed on HFD for 5 weeks. Interestingly, daily injection of AICAR, an activator of AMPK, abolished the increases in PWV, blood pressure, and blood glucose in KL+/‐ mice fed on HFD. AICAR not only abolished the downregulation of pAMPKα, peNOS, and Mn‐SOD levels but also attenuated the increased levels of collagen I, Runx2, TGFβ1 and superoxide, elastic lamellae breaks, and calcification in aortas in KL+/‐ mice fed on HFD.Conclusions: Klohto deficiency promotes HFD‐induced arterial stiffening and hypertension. The promoting effects of klotho deficiency on arterial stiffening may be due to downregulation of AMPKα activity.Grant Funding Source: Supported by HL105302 and HL 102074.