Abstract P3008: Endothelial Stearoyl-CoA Desaturase-1 Catalyzes Fatty Acid Metabolites To Mitigate Arterial Inflammation And Stiffness

Abstract

Introduction: Vascular metabolic plasticity is intimately linked with endothelial homeostasis. Stearoyl-CoA desaturase-1 (SCD1), the enzyme that catalyzes the saturated long-chain fatty acids (FA) into monounsaturated FA (MUFA), is responsive to pulsatile shear stress (PSS), and is associated with cancer cell metabolism. We assessed whether exercise-mediated PSS activates PPARγ-SCD1 to mediate anti-inflammatory metabolites for vascular protection. Methods and Results: Human aortic endothelial cells (HAEC) were subjected to PSS (τ avg = 23±8 dyne/cm 2 at 1 Hz) for 4 hours, followed by metabolomic analysis. SCD1-mediated fatty acid metabolites, azelaic acid (AZA) and oleic acid (OA), were identified to mitigate NFκB luciferase activity and monocyte binding ( p < 0.05, n= 5, vs. static condition). PSS upregulated PPARγ and SCD1 mRNA expression, whereas knockdown of PPARγ using siRNA downregulated SCD1. Wild type mice (C57BL/6J) undergoing 2-wk voluntary exercise developed increased perinuclear SCD1 expression in the aortic endothelium ( p < 0.05, n=6, vs. sedentary controls), whereas SCD1 expression was reduced in PPARγ -dominant negative mice following exercise. LDLR -/- mice with endothelial-specific SCD1 deletion (SCD1 EC-KO : Cdh5 Cre , Scd1 f/f ) on 4-wk high-fat diet (HFD) developed significantly increased VCAM-1 and Oil Red O positive lesions in the aortic arch, whereas exercise or selective overexpression (OE) of SCD1 in endothelial cells by pAd5/F35/CD144 adenoviral vector mitigated the lesions ( p < 0.05, n=5, HFD + exercise or HFD+Ad-SCD1 vs. HFD). Arterial stiffness as measured by Pulse Wave Velocity of the left common carotid was elevated in LDLR -/- SCD1 EC-KO on HF diet, but was decreased with exercise or SCD1 OE. Conclusion: PPARγ-SCD1 signaling is flow-responsive to mitigate arterial inflammation and stiffness. Despite SCD1-associated cancer cell metabolism, endothelial-specific SCD1 confers vascular protection, consistent with the reported skeletal muscle-specific model. Thus, we demonstrate that exercise activates PPARγ-SCD1 and SCD1 catalyzes AZA and OA as biomarkers with therapeutic potential.