Stimulatory effect of unsaturated fatty acids on the level of plasminogen activator inhibitor‐1 mRNA in cultured human endothelial cells

Karikó, Katalin; Rosenbaum, H.; Kuo, Alice; Zurier, Robert B.; Barnathan, Elliot S.

doi:10.1016/0014-5793(95)00170-e

Cited by 23 publications

(10 citation statements)

References 32 publications

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“…The reason for the lack of difference between 3 and 6 treatment groups in some studies could be the increasing effect of not only 3 but also 6 unsaturated fatty acids on PAI-1 production seen in vitro. [11][12][13] The observations in the present study, in which dietary intake of unsaturated fatty acids is positively associated with PAI-1 activity, also support this idea. The few studies demonstrating a reduction of PAI-1 after 3 supplementation were methodologically questionable (there was lack of a control group and placebo, 20 and PAI-1 was measured in serum 21 ).…”

Section: Discussionsupporting

confidence: 77%

“…These results are contradictory in the sense that high PAI-1 levels are regarded as a risk factor for cardiovascular disease and that high intake of unsaturated fatty acids is believed to be protective. The mechanisms behind the cross-sectional associations in the present study may be the increased production of PAI-1 by unsaturated fatty acids [11][12][13] but not by saturated fatty acids, 13 as observed in vitro.…”

Section: Discussionmentioning

confidence: 70%

“…The increased PAI-1 levels observed after 3 supplementation are paradoxical, inasmuch as long-chain 3 fatty acids are generally believed to have a cardioprotective effect. Recently, in vitro experiments have shown that unsaturated fatty acids of different degrees of unsaturation increase the production of PAI-1, [11][12][13] whereas saturated fatty acids do not. 13 To date, there is no study to support these results in vivo in humans.…”

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confidence: 99%

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Plasminogen Activator Inhibitor-1 and Relations to Fatty Acid Composition in the Diet and in Serum Cholesterol Esters

Byberg

Smedman

Vessby

et al. 2001

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Abstract-High plasminogen activator inhibitor (PAI)-1 levels and poor dietary fat quality are potential risk factors for cardiovascular disease. The aim was to investigate the cross-sectional associations between PAI-1 activity and dietary nutrient intake, focusing on fat quality, in a population-based study of 871 men aged 70 years. The relationship between PAI-1 and the fatty acid composition in serum cholesterol esters (nϭ381 men) was also studied. The estimated total fat intake was positively associated with PAI-1 activity. The intake of both monounsaturated and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas the intake of saturated fatty acids was not. In serum cholesterol esters, higher proportions of palmitoleic and dihomo-␥-linolenic acid, a lower proportion of linoleic acid, and reduced estimated ⌬5-desaturase activity were associated with higher PAI-1 levels. These associations were confounded by factors representing the insulin resistance syndrome. PAI-1 activity was positively associated with ␥-linolenic and arachidonic acid, independent of potential confounders. In conclusion, this study demonstrates that dietary intake of unsaturated fatty acids is positively associated with PAI-1 activity, whereas intake of saturated fatty acids is not. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters are partly influenced by metabolic syndrome-related factors. Key Words: plasminogen activator inhibitor-1 Ⅲ fatty acid composition Ⅲ diet Ⅲ serum cholesterol esters Ⅲ population-based study I schemic heart disease and cerebrovascular disease are the 2 leading causes of death in the industrialized world. 1 The role of dietary fat quality in cardiovascular disease is under due investigation. It has been suggested that unsaturated fatty acids reduce the risk of cardiovascular disease, whereas saturated fatty acids seem to be deleterious. 2 Also, the role of coagulation and fibrinolytic factors in cardiovascular disease is discussed. In many conditions involving an increased risk of cardiovascular disease, such as type II diabetes and glucose intolerance, there is a tendency to hypercoagulation, hypofibrinolysis, or a combination of both. A high level of plasminogen activator inhibitor (PAI)-1, the main regulator of the fibrinolytic system, has been suggested as one of the important factors involved in the genesis of atherothrombosis in conditions involving a high risk of cardiovascular disease. 3 The regulation of PAI-1 levels includes genetic and environmental factors. 3 Possible important environmental factors that vary along with PAI-1 are as follows: central obesity; concentrations of plasma insulin, proinsulin, and triglyceriderich lipoprotein particles; and dietary habits. Observational studies have demonstrated inverse associations between PAI-1 levels and the intake of carbohydrates 4 and of fibers. 4,5 The intake of fat 4 and alcohol consumption 6,7 were positively associated with PAI-1. Studies investigating the effect...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

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Plasminogen Activator Inhibitor-1 and Relations to Fatty Acid Composition in the Diet and in Serum Cholesterol Esters

Byberg

Smedman

Vessby

et al. 2001

ATVB

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“…Our results are consistent with those of others that demonstrate increased expression of PAI-1 by FFAs of varying chain length and saturation. 4,23,24 Thus, the effect of fatty acids on the expression of PAI-1 appears to be related to the prevailing concentration of diverse FFAs rather than to the concentration of a specific fatty acid.…”

Section: Discussionmentioning

confidence: 99%

Identification and Localization of a Fatty Acid Response Region in the Human Plasminogen Activator Inhibitor-1 Gene

Chen

Billadello

Schneider

2000

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Abstract-The increased expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with increased concentrations of fatty acids in blood and may accelerate atherogenesis in diabetes. The present study was designed to define mechanisms by which nonesterified (free) fatty acids (FFAs) augment the expression of PAI- Key Words: Diabetes mellitus Ⅲ PAI-1 Ⅲ free fatty acids Ⅲ Sp1 P lasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of plasminogen activators, is increased in blood in patients with diabetes mellitus. 1 Altered lipid metabolism is associated with increased concentrations of triglycerides and nonesterified (free) fatty acids (FFAs) in these subjects. 2 We have found that the infusion of glucose and emulsified triglycerides (in combination with heparin to increase FFA concentrations) into healthy human subjects increases the concentration of PAI-1 in blood. 3 Further, the exposure of cells to triglycerides increases elaboration of PAI-1 protein secondary to increased transcription. 4 -6 In previous work, we found that the effect of triglycerides on expression of PAI-1 appears to be mediated, at least in part, by their constituents: FFAs. 7 Both FFAs and their metabolites, particularly long-chain acyl-CoA, have been shown to regulate the expression of genes through binding to or modification of transcription factors. 8 -11 We postulated that the induction of PAI-1 by FFAs is secondary to a direct or an indirect effect of FFAs on the expression and/or activation of a transcription factor or factors that bind to a cis-acting element in the 5Ј flanking region of the PAI-1 gene. The present study was designed to identify the cis-acting element or elements. Methods Cell CultureHuman hepatoma (HepG2) cells were obtained from American Type Culture Collection and grown in minimal essential media (MEM; GIBCO BRL) with 10% NuSerum (GIBCO BRL). Experiments were performed in DMEM with Ham's nutrient mixture F12 (DME-F12; GIBCO BRL).The sodium salts of FFAs (Sigma Chemical Co) were dissolved in water at 37°C and added dropwise to 1% fatty acid-free bovine serum albumin (FAF-BSA; Sigma Chemical Co) in DME-F12. We determined that 3% BSA in DME-F12 contains 0.45 mmol/L FFAs (Wako NEFA C kits; Biochemical Diagnostics). All solutions were adjusted to pH 7.4 and filtered through a 0.22-m filter.Eighty percent confluent HepG2 cells were preincubated in serum-free DME-F12 for 4 to 8 hours. Subsequently, cells were exposed to DME-F12 with FAF-BSA, DME-F12 with FAF-BSA to which selected fatty acids were added, or DME-F12 with BSA. Conditioned media were collected after selected intervals and assayed for PAI-1 by ELISA (Tintelize; Biopool). Total cellular RNA was isolated conventionally with TRIzol Reagent (GIBCO BRL). Northern blotting was performed as previously described with 10 g RNA. 12 Construction of PAI-1 Promoter-Luciferase Reporter PlasmidsA 1387-bp KpnI fragment containing 1313 bp of 5Ј-flanking (Ϫ1313) and 74 bp of the untranslated first exon (ϩ74) of human PAI-1 DNA was...

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“…Furthermore, it could be speculated that fatty acids derived from VLDL triglycerides are the actual mediator, resulting in an enhanced release of PAI-1. Indeed, in vitro experiments have demonstrated that docosahexaenoic acid and dihomogamma linolenic acid induce PAI-1 mRNA in HUVECs 14 and that linoleic acid enhances PAI-1 secretion from HepG2 cells. 10 In agreement with the in vitro data, administration of n-3 fatty acids in vivo has resulted in increased plasma PAI-1 activity.…”

mentioning

confidence: 99%

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

Nilsson

Banfi

Diczfalusy

et al. 1998

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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.)

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Stimulatory effect of unsaturated fatty acids on the level of plasminogen activator inhibitor‐1 mRNA in cultured human endothelial cells

Cited by 23 publications

References 32 publications

Plasminogen Activator Inhibitor-1 and Relations to Fatty Acid Composition in the Diet and in Serum Cholesterol Esters

Plasminogen Activator Inhibitor-1 and Relations to Fatty Acid Composition in the Diet and in Serum Cholesterol Esters

Identification and Localization of a Fatty Acid Response Region in the Human Plasminogen Activator Inhibitor-1 Gene

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

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