Linoleic Acid Increases Lectin-Like Oxidized LDL Receptor-1 (LOX-1) Expression in Human Aortic Endothelial Cells

Abstract

Results from in vitro studies suggest that selected fatty acids, and especially linoleic acid (LA), can elicit endothelial dysfunction (ED). Because LA is increased in all LDL subfractions in patients with type 2 diabetes, this alteration may contribute to ED associated with diabetes. Lectin-like oxidized LDL receptor-1 (LOX-1) is the major endothelial receptor for oxidized LDL (oxLDL), and uptake of oxLDL through LOX-1 induces ED. To evaluate whether LA may contribute to the upregulation of endothelial LOX-1 in diabetes, we studied the effect of LA on LOX-1 expression in cultured human aortic endothelial cells ( E ndothelial dysfunction (ED), a characteristic feature of early-state atherosclerosis, is well documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes (1,2). Critical factors that may induce activation and injury to the endothelium in the diabetic state include oxidized LDL (oxLDL) (3) and selected unsaturated fatty acids, such as linoleic acid (LA) (4). One potential key determinant of oxLDL-induced ED is lectin-like oxidized LDL receptor-1 (LOX-1), a newly identified limiting factor for oxLDL uptake by endothelial cells (5). Data showing that LOX-1 expression is enhanced by proatherogenic factors relevant to human diabetes, including oxLDL (6), high glucose (7), advanced glycation end products (8), and C-reactive protein (9), and is upregulated in endothelium and aortas of diabetic animals (8) support a role of this receptor in the pathogenesis of diabetic vascular dysfunction. Substantial amounts of data have been accumulated to show that LA is a pro-oxidative and proinflammatory molecule (10 -12) that can induce endothelial cell activation and dysfunction. These data and the observation that patients with type 2 diabetes show increased concentrations of LA in all LDL subfractions (13) support the significance of this fatty acid in ED associated with diabetes. In the present study, we investigated the role of LA in the regulation of endothelial LOX-1, the molecular mechanisms involved in this effect, and the role of LOX-1 in LA-induced oxLDL uptake by endothelial cells. RESEARCH DESIGN AND METHODS

Diabetic Vasculopathy and the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1)

“…Recently, we investigated the role of linoleic acid in the regulation of endothelial LOX-1, the molecular mechanisms involved in this effect and the role of LOX-1 in linoleic acidinduced oxLDL uptake by HAECs. Our results demonstrated that treatment of endothelial cells with linoleic acid, at concentrations similar to those found in diabetic patients [76], increases, in a timeand dose-dependent manner, endothelial LOX-1 [77]. This effect was inhibited by antioxidants and inhibitors of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase, thus indicating a role of oxidative stress in linoleic acid-induced endothelial LOX-1 expression and identifying NADPH oxidase as one of the enzymatic superoxide sources activated by linoleic acid.…”

“…Because LOX-1 is the major receptor for oxLDL expressed in endothelial cells, presumably mediating the majority of the uptake of oxLDL by these cells, induction of endothelial LOX-1 may represent a new mechanism by which fatty acids promote endothelial dysfunction. Our finding that up-regulation of LOX-1 by linoleic acid is associated with enhanced uptake of oxLDL uptake by endothelial cells supports this possibility [77]. Endothelial dysfunction can be described as impairment in the generation and function of NO.…”

Metformin reduces endothelial cell expression of both the receptor for advanced glycation end products and lectin-like oxidized receptor 1

“…Finally, high levels of glucose were shown to enhance LOX-1 [3,25], although Chen et al [26] did not observe such an effect, but were unable to modify endothelial RAGE expression. By return, activation of these 2 receptors results in the intracellular enhancement in ROS formation [27][28][29], and to the activation of the above-mentioned redox transduction/ transcription pathways [25,17], thus contributing to the vicious circle of endothelial dysfunction in the diabetic state.…”

LOX-1, Oxidative Stress and Inflammation: A Novel Mechanism for Diabetic Cardiovascular Complications

“…These unsaturated fatty acids can elicit endothelial dysfunction and are closely linked with atherogenesis. Maingrette et al found that linoleic acid enhanced, through LOX-1 activation, ox-LDL uptake by endothelial cells with involvement of NF-κB [67]. It is probable that linoleic acid is an important metabolic factor that participates in the development of diabetic atherosclerosis through activation of LOX-1/NF-κB pathway.…”