Unsaturated Fatty Acids Increase Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells

Abstract

Abstract-In vivo studies have demonstrated a strong positive correlation between plasma very low density lipoprotein (VLDL) triglyceride and plasma plasminogen activator inhibitor-1 (PAI-1) activity levels. Furthermore, VLDL has been shown to induce PAI-1 secretion from cultured endothelial cells. In contrast, no or variable effects on PAI-1 secretion have been reported for native low density lipoprotein. It could be speculated that fatty acids derived from VLDL triglycerides are the actual mediators, resulting in an enhanced secretion of PAI-1. In the present study, we have analyzed the effects of both saturated and unsaturated fatty acids on PAI-1 expression and secretion by endothelial cells. Addition of 0 to 50 mol/L of either palmitic acid or stearic acid had no effect on PAI-1 secretion from human umbilical vein endothelial cells or EA.hy926 cells. In contrast, addition of oleic acid, linoleic acid, linolenic acid, and eicosapentaenoic acid resulted in a significant increase in PAI-1 secretion from both cell types. Northern blot analysis of PAI-1 mRNA levels was in agreement with these findings. Transfection experiments demonstrated that addition of linolenic acid and eicosapentaenoic acid significantly increased PAI-1 transcription. The fatty acid response region was localized to a previously described VLDL-inducible region of the PAI-1 promoter. Electromobility shift assays demonstrated that unsaturated fatty acids induced the same complex as did VLDL, whereas saturated fatty acids had no effect. Furthermore, it was demonstrated that the activation procedure did not involve fatty acid oxidation to any significant extent. In conclusion, the present study demonstrates that unsaturated fatty acids increase PAI-1 transcription and secretion by endothelial cells in vitro. The effect appears to be mediated by a previously described VLDL-inducible transcription factor. (Arterioscler Thromb Vasc Biol. 1998;18:1679-1685.)

Birth weight and the insulin resistance syndrome: association of low birth weight with truncal obesity and raised plasminogen activator inhibitor-1 but not with abdominal obesity or plasma lipid disturbances

“…Non-esterified fatty acids also suppress nitric oxide production in vitro [35] and this could increase blood pressure [36]. The production of PAI-1 is induced by NEFA, a process which possibly involves induction of gene transcription by intracellular fatty acids [37].…”

Type 2 Diabetes and Fibrinolysis

“…The fibrates decrease PAI-1 production stimulated by insulin in hepatocytes in vitro. (Alessi & Juhan-Vague, 2006;Alessi et al, 2007;Asplund-Carlson et al, 1993;Eriksson et al, 1998;Li et al, 1997;Nilsson et al, 1998;Schneider & Sobel, 1996;Stiko-Rahm et al, 1990). …”

Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

“…5,6 NEFAs have been shown to induce both hepatic and peripheral IR, 7,8 to activate apoptotic pathways in pancreatic b cells, 9 to promote endothelial dysfunction 10 and to increase the production of plasminogen activator inhibitor-1. 11 Most importantly, increased NEFA supply of the liver, primarily owing to the incomplete insulin-mediated suppression of lipolysis in this type of subjects, is the initial step for the development of the characteristic lipid disorders of the metabolic syndrome. 12 With regard to hypertension, several studies have clearly shown a causal association of IR and compensatory hyperinsulinaemia with blood pressure (BP) elevation, through mechanisms like sodium retention, stimulation of the sympathetic nervous system, promotion of vascular cell's growth or impairment of insulin-mediated vasodilatation in insulin-resistant states.…”