Abstract 862: SGK-1 Metabolically Reprograms VSMC Energy Metabolism by Modulation of Substrate Utilization and Mitochondrial Structure

Abstract

Obesity is associated with vascular remodeling which increases the risk of developing heart disease; the leading cause of death world-wide. The mechanisms underlying vascular remodeling during obesity are not completely understood, but impaired cellular energy metabolism is thought to play an important role. Oxidative phosphorylation (OXPHOS) and glycolysis are the cell’s two main energy generating pathways that rely on energy substrate availability. Glucose is the primary substrate for glycolysis, whereas, pyruvate which is metabolized from glucose, long chain fatty acids (LCFAs) and glutamine are the substrates metabolized for OXPHOS. Previously, we reported that serum and glucocorticoid-inducible kinase 1 (SGK-1) is up-regulated in the vasculature of diet-induced obese mice, implicating a role for this serine/threonine kinase in obesity-related vascular remodeling. Indeed, our current data demonstrate that deletion of serum and glucocorticoid-inducible kinase 1 (SGK-1) specifically in vascular smooth muscle cells (VSMC) protects against obesity-induced vascular remodeling. Further, protection from remodeling was concomitant with metabolic reprogramming of VSMCs due to a metabolic shift from glycolysis towards OXPHOS in SGK-1 knockout (KO) VSMCs compared to wildtype (WT) VSMCs. Interestingly, metabolic reprogramming was also evident in SGK-1 KO VSMC under basal conditions, suggesting a novel role for SGK-1 in cellular energy metabolism. Inhibition of glycolysis was due to an overall reduction in glucose uptake, whereas, an increase in OXPHOS was associated with redistribution of mitochondria and altered levels of the mitochondrial fusion and fission regulatory proteins, suggesting that SGK-1 reprograms energy metabolism through modulation of energy substrate utilization and mitochondrial structure. Altogether, our data point to SGK-1 inhibition as a novel therapy for obesity-related vascular pathology.