Abstract 19596: Endothelial Acyl-CoA Synthetase 1 is not Required for Saturated Fatty Acid- Mediated Inflammatory and Apoptotic Effects
Saturated fatty acids, such as palmitic (C16:0) and stearic acid (C18:0), cause detrimental effects in endothelial cells (ECs) that might contribute to macrophage accumulation in adipose tissue and the vascular wall in states of obesity and insulin resistance. Fatty acids require conversion into acyl-CoA derivatives to exert most biological effects, a reaction catalyzed by acyl-CoA synthetases (ACSL). We hypothesized that endothelial deficiency of ACSL1, an ACSL isoform mediating inflammatory effects in myeloid cells, would protect from detrimental effects of saturated fatty acids in vitro and saturated fat feeding in vivo. Mouse microvascular CD45-negative-CD31-positive endothelial cells (MMECs) were isolated from lungs or hearts by fluorescence activated cell sorting. In these cells and in bovine aortic ECs (BAECs), saturated fatty acids caused JNK activation, ER stress, and apoptosis, along with increased inflammatory activation, as measured by an increase in the release of the soluble adhesion molecules sICAM-1 (p<0.01), and sVCAM-1 (p<0.01), as well as release of the chemokine CCL2 (p<0.05). In order to evaluate the role of endogenous ACSL1 in ECs, a conditional endothelial Acsl1-deficient mouse model was generated. Acsl1-deficient MMECs had significantly decreased beta-oxidation as measured by decreased acid soluble metabolite production (WT 393.1 ± 25.6, KO 270.5 ± 16.3 cpm/µg protein; p<0.05). However, conditional endothelial ACSL1-deficiency did not protect against the inflammatory or apoptotic effects of saturated fatty acids in vitro, nor did it protect insulin resistant mice fed a saturated fatty acid-rich diet from epididymal adipose tissue accumulation of macrophages or increased aortic adhesion molecule expression. Conversely, forced Acsl1 overexpression in BAECs exacerbated the effects of saturated fatty acids on apoptosis and ER stress, in part through increased JNK activation. In conclusion, forced overexpression of Acsl1 can exacerbate some effects of saturated fatty acids; however, endogenous ACSL1 is not required for pro-inflammatory or pro-apoptotic responses of ECs to saturated fatty acids.
- © 2012 by American Heart Association, Inc.