Eicosapentaenoic Acid Prevents Saturated Fatty Acid-Induced Vascular Endothelial Dysfunction: Involvement of Long-Chain Acyl-CoA Synthetase.

Abstract

Vascular endothelial dysfunction is considered an early predictor of atherosclerosis. It has been proven that elevated blood levels of free fatty acids pose a substantial risk for the development of cardiovascular disease. In this study, we examined the effects of palmitic acid (PA), a saturated fatty acid, on endothelial function by using the expression of adhesion molecule, cytokines, and inflammatory protein as indicators, as well as investigated the effects of eicosapentaenoic acid, an n-3 polyunsaturated fatty acid. Human umbilical vein endothelial cells (HUVEC) were exposed to PA and EPA. When HUVEC were exposed to PA, there was an increase in the expression of adhesion molecule, cytokines, and inflammatory protein (ICAM-1, MCP-1, interleukin-6, PTX3). PA augmented the expression of long-chain acyl-CoA synthetase (ACSL) and the cyclin-dependent kinase inhibitor p21, and enhanced the phosphorylation of p65, a component of NF-κB. ACSL inhibition and siRNA-mediated ACSL3 knockdown suppressed the PA-induced increase in the expression of adhesion molecule, cytokines, and inflammatory protein, and ACSL inhibition suppressed the enhancement of p65 phosphorylation. In addition, p21 knockdown suppressed the PA-induced increase in the expression of MCP-1 and ICAM-1. EPA suppressed the PA-induced increase in the expression of ACSL and p21, the enhancement of p65 phosphorylation, as well as the associated increase in the expression of ICAM-1, MCP-1, interleukin-6, and PTX3. These results suggest that the ACSL, p21, and NF-κB-dependent pathway may possibly be involved in PA-induced vascular endothelial dysfunction, and that EPA ameliorates this at least in part through the regulation of ACSL3 expression.