SGK1 Signaling Pathways in Vascular Remodeling

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DESCRIPTION (provided by applicant): Aberrant vascular smooth muscle cells (SMC) proliferation and survival is a hallmark vascular pathology underlying atherosclerosis and restenosis following vascular injury. Mitogenic signaling cascades that become activated upon injury stimulate serine/threonine protein kinases that rapidly regulate the phosphorylation of key genes and regulatory proteins that control cell cycle progression and cell survival processes. In this regard, emerging data indicate that the activity of serum and glucocorticoid inducible kinase 1 (SGK1) is linked to changes in cellular proliferation and survival processes in tumor cells. Although much progress has been made regarding the role of SGK1 in epithelial cell biology; its role in vascular smooth muscle cell function and in the development of lesion formation; in particular, is completely unknown. We have shown that over-expression of activated SGK1 induces a proliferative and survival phenotype in A7r5 rat aortic SMC. This correlated with an acceleration of cell cycle progression owing to an increase in G1 to S transition. Further, we found that SGK1 activity is enhanced in injured carotid arteries. To elucidate the molecular mechanism underlying these effects, we conducted a kinase substrate protein microarray to screen for novel SGK1 targets. Our initial studies identified the mitochondrial deacetylase, Sirt3 as a putative SGK1 target. In light of these findings, we hypothesize that SGK1 promotes neointimal lesion development in vivo by stimulating vascular SMC growth and inhibiting vascular SMC apoptosis via a mechanism that relies upon SGK1-mediated phosphorylation of Sirt3 and modulation of mitochondrial function. To test this hypothesis, we established a unique SMC-specific SGK1 knockout mouse model. We will use SMC isolated from this model as well as SMC stable cell lines in loss- and gain-of-function experiments. In addition, we will utilize these resources as we examine the following specific aims: 1) to test the hypothesis that vascular SMC-targeted knockout of SGK1 attenuates the development of neointimal formation in response to wire-induced vascular injury, 2) to test the hypothesis that SGK1 can directly phosphorylate Sirt3 and thereby regulate its protein function, 3) to demonstrate that a SGK1/Sirt3 signaling pathway is a critical determinant of vascular SMC growth and survival. PUBLIC HEALTH RELEVANCE: This proposal seeks to identify SGK1 as an important mediator of vascular occlusion that occurs as a consequence of arterial stenting or angioplasty. In addition, it will provide insight into the molecular mechanisms responsible for the actions of SGK1 in vascular smooth muscle cells. Ultimately, these studies may identify SGK1 as a novel therapeutic target for occlusive vascular diseases that occur as a consequence of atherosclerosis, restenosis or hypertension.