Secreted Klotho Protects Against Aging‐associated Coronary Endothelial Dysfunction via SIRT1 Activation

Abstract

Background and ObjectiveCoronary heart disease (CHD) is the leading cause of death in the world. Endothelial dysfunction is an initial step in the development of CHD and may be a critical early target for the prevention of CHD. Klotho, originally identified as an aging‐suppressor gene, is predominately expressed in kidneys. Klotho protein is secreted into the circulation. The objective of this study is to investigate whether secreted Klotho protein protects against aging‐associated coronary endothelial dysfunction and CHD.Methods and ResultsWe found that aging‐associated coronary endothelial dysfunction assessed by endothelium‐dependent vasodilation and coronary blood flow was accompanied by a reduction in serum level of secreted Klotho (sKL) protein. Using klotho‐hypomorphic (KL (−/−)) mice, we confirmed that Klotho deficiency caused coronary endothelial dysfunction. Interestingly, the impaired endothelium‐dependent vasorelaxation and coronary flow were remarkably improved by in vivo delivery of exogenous sKL protein in aged mice and KL (−/−) mice, suggesting that sKL rescued aging‐induced coronary artery endothelial dysfunction. In addition, sKL treatment protected against aging‐associated and Klotho deficiency‐induced cardiac dysfunction, as evidenced by restoration of stroke volume and cardiac output in aged and KL (−/−) mice. sKL treatment also enhanced coronary endothelial nitric oxide bioavailability and attenuated oxidative stress and apoptosis. Mechanistically, aging via Klotho deficiency suppressed SIRT1‐AMPKα‐eNOS pathway in the coronary endothelial cell through activation of transcription repressor HIC‐1. Furthermore, pharmacological activation of SIRT1 by SRT 1720 protected against Klotho deficiency‐induced coronary artery endothelial dysfunction and cardiac dysfunction.ConclusionKlotho regulates coronary artery endothelial function via SIRT1 activation. Supplement of exogenous Klotho protein represents a promising therapeutic strategy for the treatment of aging‐associated coronary heart disease.Support or Funding InformationAG049780, HL118558This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.