Abstract 9367: Palmitic Acid-Induced Osteogenic Differentiation of Vascular Smooth Muscle Cells is Mediated by ACSL3- and NF-κB-Dependent Pathways and Prevented by Eicosapentaenoic Acid
Background: Elevated plasma free fatty acids (FFAs) play a central role in development of atherosclerosis in obesity and type 2 diabetes. Increasing evidence indicates that FFAs activate inflammatory signaling pathways in vascular cells, including macrophages and vascular endothelial cells. It has long been recognized that vascular calcification is highly prevalent in type 2 diabetes and contributes to the increased mortality in these patients. However, it remains to be determined whether FFAs directly induce vascular calcification. In this study, we examined the effects of saturated fatty acids on osteogenic differentiation and apoptosis of human aortic smooth muscle cells (HASMC), and the protective effects of eicosapentaenoic acid (EPA), a major n-3 polyunsaturated fatty acid, on such palmitic acid (PA)-induced vascular calcification.
Methods and Results: PA induced expression of osteogenic genes such as bone morphogenetic protein-2 (BMP2) and Msx2 in HASMC. PA increased Smad1 and Smad4 expression, and concomitantly decreased Smad6 expression, all of which are critical transducers of BMP2 signal pathway. Inhibitors of either acyl-CoA synthetase (ACS) or NF-κB prevented PA-induced expression of osteogenic genes. Among the long-chain acyl-CoA synthetase (ACSL) subfamily, ACSL3 expression was predominant in HASMC, and was further increased by PA. Knock-down of ACSL3 expression with siRNA attenuated PA-induced expression of BMP2 and Msx2, suggesting that ACSL3 plays an important role in PA-induced osteogenic differentiation of HASMC. Furthermore, PA elevated phospho-NF-κB-p65, which was prevented by ACS inhibitor and ACSL3 siRNA. EPA prevented PA-induced expression of osteogenic genes, Smads1/4 and ACSL3, and phosphorylation of NF-κB-p65. In addition, high concentration of PA induced activation of caspase-3 and calcium deposition in HASMC, both of which were attenuated by EPA.
Conclusions: Our results demonstrate that PA-induced osteogenic differentiation and calcium deposition in vascular smooth muscle cells are mediated by ACSL3- and NF-κB-dependent pathways, and indicate that EPA prevents these changes at least in part by interfering with PA-induced ACSL3 expression.
- © 2010 by American Heart Association, Inc.