EC-SGK1 and EnNaC mediate vascular stiffening
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Vascular stiffening is an independent predictor of cardiovascular diseases, the leading cause of death worldwide. High dietary salt intake has been shown to increase vascular stiffness in humans, especially in salt-sensitive populations. To date, the underlying mechanisms of salt-sensitivity related vascular stiffening remain poorly understood. In this study, we aim to examine the role of the endothelial sodium channel (EnNaC), and its upstream regulator, serum and glucocorticoid regulated kinase 1 (SGK1) in salt-sensitivity related EC and arterial stiffening. To probe signaling pathways, we combined both in vivo (e.g. pulse wave velocity) and in vitro (e.g. atomic force microscopy) approaches and used a variety of experimental models including mice with [alpha]EnNaC deletion, mice treated with a pharmacological mTOR (a upstream target of both [alpha]EnNaC and SGK1) inhibitor, mice with global SGK1 deletion, mice with EC selective SGK1 deletion, and to a more clinical perspective, primary human aortic ECs treated with a pharmacological SGK1 inhibitor. Importantly, our study has showed that deficiency/inhibition of EnNaC or EC-SGK1 prevented/attenuated salt-sensitivity related EC and arterial stiffening, suggesting a therapeutic potential of targeting EnNaC and EC-SGK1 expression in salt-sensitivity related cardiovascular dysfunction. Nevertheless, whether this is directly mediated through EC-SGK1 regulation of EnNaC requires further examination.
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Ph. D.