Abstract 17853: Activation of AMP-activated Protein Kinase (AMPKα) by AICAR Attenuates Klotho Deficiency-induced Endothelial Dysfunction, Arterial Stiffening and Hypertension

Abstract

Background: Arterial stiffening and hypertension are progressive aging-related disorders. Klotho (KL) is a recently-discovered anti-aging gene but its role in the pathogenesis of endothelial dysfunction, arterial stiffening and hypertension is not fully understood. Methods and Results: Heterozygous Klotho deficiency ( KL +/- ) mice and WT littermate mice were fed on high fat diet (HFD) or normal diet (ND). Plasma KL in KL heterozygeous mice (+/-) is about a half of that of the WT mice. Pulse wave velocity (PWV), an index of arterial stiffening, was increased in KL +/- mice but not in WT mice fed on HFD for 4 weeks. Systolic blood pressure and blood glucose levels were increased earlier with greater magnitudes in KL +/- mice than in WT 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 endothelial dysfunction, arterial stiffening and hypertension. The promoting effects of klotho deficiency on arterial stiffening may be due to downregulation of endothelial AMPKα activity.