Abstract 19086: Pulsatile Shear Stress-mediated Fatty Acid Metabolites Promote Anti-oxidant Effects
Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. While oscillatory shear stress (OSS) preferentially develops at the lateral wall of arterial bifurcations and induces oxidative stress and inflammatory states, pulsatile shear stress (PSS) develops in the straight portions of the vasculature to oppose the effects and promote “athero-protection”. In this context, we hypothesize that PSS activates PPAR-γ to produce athero-protective fatty acid metabolites to attenuate oxidative stress. Metabolomic analysis performed for 155 metabolites from human aortic endothelial cells exposed to PSS (τavg= 23±8 dyne/cm2 at 1 Hz for 4 hrs) revealed a significant increase in anti-inflammatory metabolites, including fatty acids such as oleic acid (OA) and dicarboxylic acids such as azelaic acid (AzA) (1.43±0.73-fold, 2.03±0.54-fold vs. control, respectively, p < 0.05, n=6), and up-regulated metabolism-related genes including SCD1 and PPAR-γ (1.42±0.14-fold, 1.53±0.32-fold vs. control, respectively, p < 0.001, n=6). SCD1 produces oleic acid, and SCD1 mRNA expression was down-regulated by siPPAR-γ (0.66±0.17-fold, vs. PSS, p < 0.05, n=4). AzA, a known PPAR-γ agonist and a breakdown product of oleic acid, down-regulated VCAM and ICAM (0.31±.09-fold, 0.18±.01-fold vs. control, respectively, p<0.05, n=4) when treated with AzA alone. AzA attenuated H2O2-induced VCAM and ICAM mRNA expression (0.36±0.10-fold, 0.38±0.20-fold, respectively, p<0.05, n=4). The role PSS on PPAR- γ activation was further recapitulated in a model for paroxysmal atrial fibrillation (Afib) in New Zealand White rabbits. The right atrium was paced at 800 bpm (cycle length (CL) = 75 ms) to produce an irregular ventricular response of a mean rate of 200 bpm (CL = 300 ms) to simulate atrial fibrillation for 4 hours. p-PPAR- γ staining in the athero-prone aortic arches vs. athero-protective descending aortas was decreased in response to a reduction in time-averaged shear stress (from τavg = 32.0±2.4 dyne/cm2 to τavg = 22.7±3.5 dyne/cm2). Overall, pulsatile shear stress-induced fatty acid metabolites impart anti-oxidant effects to maintain endothelial homeostasis, implicating the role of PPAR-γ-SCD1-OA-AzA pathway.
Author Disclosures: N. Jen: None. J. Tang: None. J. Gau: None. O.A. Ajijola: None. R. Li: None. T.K. Hsiai: None.
- © 2015 by American Heart Association, Inc.