Effects of Native, Triglyceride-Enriched, and Oxidatively Modified LDL on Plasminogen Activator Inhibitor-1 Expression in Human Endothelial Cells

Abstract

Abstract-Whereas VLDL has consistently been shown to induce a concentration-dependent increase in the expression of plasminogen activator inhibitor-1 (PAI-1) in human umbilical vein endothelial cells (HUVECs) and liver cells, variable effects have been reported for native and oxidatively modified LDL. In the present study, activation of PAI-1 protein and mRNA expression by native LDL (nLDL), UV-oxidized LDL (uvLDL), and triglyceride (TG)-enriched LDL was studied in HUVECs by using different incubation times and a wide range of lipoprotein concentrations. No significant increase of PAI-1 protein expression was observed after 4 hours of incubation with nLDL or uvLDL. However, PAI-1 protein secretion from HUVECs was markedly enhanced after 18 hours of incubation with uvLDL (200% increase at 10 g/mL). Stimulation of PAI-1 protein expression in HUVECs by nLDL was seen, however, after increasing the TG content of the LDL particle. LDL enriched in phospholipid had no effect on PAI-1 secretion. PAI-1 mRNA levels on northern blot increased in parallel with the activation of PAI-1 protein expression by native and modified forms of LDL. Low concentrations of TG-enriched LDL (10 g/mL) and higher concentrations of nLDL and uvLDL (100 g/mL) were found to increase the binding of a VLDL-inducible transcription factor to the PAI-1 promoter. These results indicate that the TG content of the LDL particle influences PAI-1 expression in endothelial cells. Low concentrations of uvLDL enhanced PAI-1 protein and mRNA expression in the HUVECs after an 18-hour incubation but did not influence the VLDL-inducible transcription factor. This suggests that low levels of oxidized LDL increase PAI-1 expression by a different mechanism than VLDL and TG-enriched LDL. (Arterioscler Thromb Vasc Biol.

Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Nonhyperlipidemic Postinfarction Patients

“…14 -16 However, regarding our finding in homozygous 4G patients of risk in association with large LDL particles, although native LDL is not thought to be a strong determinant of PAI-1 levels or responses, modified LDL (oxidized, glycated, triglyceride-rich) does appear to be active in this regard. 6 Indeed, consistent with our LDL results are findings from a report by Allison et al 17 showing that: triglycerideenriched LDL (large LDL) is a potent activator of PAI-1 protein and mRNA; potency of stimulation correlates with LDL triglyceride content; and triglyceride-enriched LDL induces the same transcription factor as VLDL. Conclusive demonstration of involvement in polymorphism-associated risk of allele-specific interactions with triglyceride-rich lipoproteins affecting acute responses in PAI-1 levels would require additional specifically focused studies.…”

Allele-Specific Regulation of Matrix Metalloproteinase-7 Promoter Activity Is Associated With Coronary Artery Luminal Dimensions Among Hypercholesterolemic Patients

“…9 Lipid peroxidation was measured by quantification of thiobarbituric acid-reactive substance specified as nanomoles malondialdehyde per milligram of protein.…”

The Renin-Angiotensin System Is Involved in the Production of Plasminogen Activator Inhibitor Type 1 by Cultured Endothelial Cells in Response to Chylomicron Remnants

“…Fatty acids (33) have an effect upon the VLDL-inducible transcription factor that is similar to that of VLDL (34). The triglyceride content of lipoprotein particles influences PAI-1 expression in endothelial cells, whereas OxLDL increase PAI-1 expression by a different mechanism than that seen with triglyceride-rich lipoproteins (35). In particular, lysophosphatidylcholine, presented in OxLDL, has been shown to stimulate PAI-1 expression (36).…”