Biomedical subjects

P Eriksson

Publications and source records attributed to P Eriksson.

At least 91 records · Page 5Linked to original sources

PubMed1999

A common functional polymorphism (C-->A substitution at position -863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha.

Tumour necrosis factor-alpha (TNF-alpha) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF-alpha has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The regulation of TNF-alpha expression in man is indicated to be partly genetically determined. We therefore screened a 1263 bp section of the proximal promoter of the TNF-alpha gene for common genetic variants affecting the transcriptional activity of the gene. Here we report the characterization of a common functional polymorphism in the promoter region of the TNF-alpha gene, a C-->A substitution at position -863. Electromobility shift assays provided evidence for a distinct difference in the binding of monocytic and hepatic nuclear factors to the -863C and -863A alleles. The rare -863A allele was associated with 31% lower transcriptional activity ( P < 0.001) in chloramphenicol acetyltransferase (CAT) reporter gene studies in human hepatoblastoma (HepG2) cells, indicating that the-863C/A polymorphism influences the basal rate of transcription of the TNF-alpha gene in vitro. Allele frequencies were 0.83/0.17 amongst 254 apparently healthy men of Swedish origin, aged 35-50 years. In 156 men, the -863C/A polymorphism was associated with the serum TNF-alpha concentration, carriers of the rare A allele having a significantly lower TNF-alpha level ( P < 0.05). It is concluded that the common-863C/A polymorphism in the promoter region of the TNF-alpha gene is functional in vitro in monocytic and hepatic cells and influences the serum TNF-alpha concentration in vivo in healthy middle-aged men.

Adult↗

PubMed1999

Continuous vectorcardiographic monitoring of ischemia during coronary angioplasty in patients with bundle-branch block.

BACKGROUND: Patients with the combination of bundle-branch block and ischemic heart disease have a poor outcome. There is no established criterion for detection of transient ischemia when bundle-branch block is present. OBJECTIVE: To elucidate vectorcardiographic changes during coronary angioplasty of patients with bundle-branch block. DESIGN AND METHODS: The QRS complex and ST-segment changes of 29 patients with bundle-branch block were studied during elective coronary angioplasty using continuous vectorcardiography. Data for the patients with bundle-branch block were compared with data for narrow-QRS-complex controls, matched for the vessel dilated, sex, and age. RESULTS: Patients with bundle-branch block were found to have more pronounced changes in the QRS-vector difference as a response to coronary occlusion than did controls. ST-vector magnitude responded in a similar way during coronary occlusion of patients with and without bundle-branch block but from different baselines. ST change-vector magnitude was found to be the most sensitive parameter for detection of ischemia in patients with bundle-branch block as well as for controls. CONCLUSION: Monitoring of transient ischemia during coronary angioplasty for patients with bundle-branch block is feasible using continuous vectorcardiography. A change in ST vector magnitude > 100 microV is suggested to indicate significant ischemia in the presence of bundle-branch block.

Aged↗

PubMed1999

Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression in vascular smooth muscle cells.

Plasminogen activator inhibitor-1 (PAI-1) functions as an important regulator of fibrinolysis by inhibiting both tissue-type and urokinase-type plasminogen activator. PAI-1 is produced by smooth muscle cells (SMCs) in atherosclerotic arteries, but the mechanisms responsible for induction of PAI-1 in SMCs are less well understood. In cultured human aortic SMCs, PAI-1 mRNA expression and protein secretion were increased after incubation with oxidized low-density lipoprotein (LDL) and the lipid peroxidation product lysophosphatidylcholine, whereas the effects of native LDL on PAI-1 production and release were more variable and did not reach statistical significance. The effect of LDL on arterial expression of PAI-1 in vivo was also studied in an animal model. Intravenous injection of human LDL in Sprague-Dawley rats resulted in accumulation of apolipoprotein B in the aorta within 12 hours as assessed by immunohistochemical testing. Epitopes specific for oxidized LDL began to develop in the aorta 12 hours after injection of LDL and peaked at 24 hours; this peak was accompanied by intense expression of PAI-1 immunoreactivity in the media. Also, increased aortic expression of PAI-1 mRNA after LDL injection was detected by using in situ hybridization. The transcription factor activator protein-1, which is known to bind to the promoter of the PAI-1 gene, was activated in the aortic wall 24 hours after LDL injection as assessed by electrophoretic mobility shift assay. Pretreatment of LDL with the antioxidant probucol decreased expression of oxidized LDL and PAI-1 immunoreactivity and activator protein-1 induction in the aorta but did not affect expression of apolipoprotein B immunoreactivity. These findings demonstrate that LDL oxidation enhances secretion of PAI-1 from cultured SMCs and that a similar mechanism may be involved in vascular expression of PAI-1.

Animals↗

PubMed1999

Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration.

Plasma fibrinogen is a major risk factor for coronary heart disease, stroke, and peripheral artery disease. There is evidence that genetic variation in the beta-fibrinogen gene contributes to the rate of synthesis of fibrinogen, but the molecular mechanism underlying the genetic heritability of the plasma fibrinogen concentration is largely unknown. We evaluated the physiological roles of 5 common nucleotide substitutions in the promoter region of the beta-fibrinogen gene at positions -148, -249, -455, -854, and -993 from the transcriptional start site. Electrophoretic mobility shift assays revealed distinct differences in the binding characteristics of nuclear proteins between wild-type and mutant fragments of both the -455G/A and -854G/A polymorphisms, whereas no clear differences were observed for the -148C/T, -249C/T, and -993C/T sites. Transfection studies in HepG2 cells showed increased basal rates of transcription for both the G-to-A substitution at position -455 (+50%, P<0.05) and the G-to-A substitution at -854 (+51%, P<0.05). Additional transfection studies using proximal promoter constructs confirmed that both the -455A and -854A alleles independently enhance the basal rate of transcription of the beta-fibrinogen gene. The rare alleles of the nonrelated -455G/A and -854G/A polymorphisms were also associated with significantly increased plasma fibrinogen levels in healthy middle-aged men. Overall, the 2 polymorphisms together explained approximately 11% of the variation in plasma fibrinogen concentration. It is concluded that the -455G/A and -854G/A polymorphisms of the beta-fibrinogen gene are physiologically relevant mutations with a significant impact on the plasma fibrinogen concentration.

Adult↗

PubMed1999

Effects of native, triglyceride-enriched, and oxidatively modified LDL on plasminogen activator inhibitor-1 expression in human endothelial cells.

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 microg/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 microg/mL) and higher concentrations of nLDL and uvLDL (100 microg/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.

Cells, Cultured↗

PubMed1999

Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells.

The consistent positive correlation between triglyceride and plasminogen activator inhibitor-1 (PAI-1) levels in plasma and the fact that very low density lipoprotein (VLDL) induces secretion of PAI-1 from cultured human umbilical vein endothelial cells (HUVECs) and human hepatoblastoma cells have raised the question of whether fibrate treatment, the main effect of which is a profound lowering of plasma concentrations of VLDL, might improve fibrinolytic function by reducing the plasma levels of PAI-1. However, the findings of controlled clinical trials using various fibrate compounds have been discrepant. ECs express PAI-1 under normal conditions in humans. We therefore examined the effects of several fibrate compounds on PAI-1 expression and secretion by cultured HUVECs and the HUVEC-derived cell line EA.hy926. All fibrate compounds examined had significant effects on PAI-1 gene transcription in the EA.hy926 cells. Low concentrations of clofibric acid and bezafibrate increased PAI-1 transcription and secretion, whereas Wy-14643 increased PAI-1 synthesis in a dose-dependent way. In contrast, both fenofibric acid and gemfibrozil markedly decreased PAI-1 transcription and secretion from HUVECs and EA.hy926 cells. Thus, stimulation of the transcriptional activity of the PAI-1 gene by some fibrates is linked to increased secretion of PAI-1 protein by the cells, whereas the opposite effects occur with other fibrate compounds. Whether the different effects on PAI-1 transcription and secretion by ECs in vitro also reflect differences in treatment effects on the regulation of plasma PAI-1 activity in vivo will have to be determined in larger-scale, controlled clinical trials.

Bezafibrate↗

PubMed1999

Ischemic stroke. Impact of a recent myocardial infarction.

BACKGROUND AND PURPOSE: The risk of ischemic stroke is increased after a myocardial infarction. We quantified the stroke risk and evaluated ischemic stroke characteristics after an acute myocardial infarction. METHODS: A case-control study including patients with first-ever stroke was undertaken. Cases (n=103) were recorded prospectively in the population-based Northern Sweden World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study. Two controls per case with a stroke but without a recent myocardial infarction were matched for age, sex, and year of stroke onset. RESULTS: The sudden onset of neurological symptoms (76.7% versus 54.9%, P<0.001), impairment of consciousness (35.0% versus 18.4%, P<0.01), and a progression in neurological deficits (19.4% versus 8.7%, P<0.01) were more common in cases, while the onset of stroke during sleep was rarer in cases (6.8% versus 21.4%, P<0.01). In cases and controls, the clinical subclasses of stroke were as follows: total anterior circulation infarcts, 51.5% versus 37.9% (P<0.05); partial anterior circulation infarcts, 28.2% versus 26.7% (P=NS); lacunar infarcts, 4.8% versus 27.2% (P<0.001); and posterior circulation infarcts, 15.5% versus 8.2% (P=0.051). During the first 28 days after myocardial infarction, the daily rate of stroke declined rapidly from approximately 9 to 1 stroke per 10 000 myocardial infarction patients compared with an age-adjusted average daily stroke rate of 0.14 per 10 000 in the MONICA population. CONCLUSIONS: We conclude that the clinical characteristics of the stroke differ between patients with and without a recent myocardial infarction. The risk of a first-ever ischemic stroke is highest during the first few days after a myocardial infarction, but it then declines rapidly, and the absolute number of stroke events is low.

Acute Disease↗

PubMed1999

VLDL activation of plasminogen activator inhibitor-1 (PAI-1) expression: involvement of the VLDL receptor.

The potential role of the very low density lipoprotein (VLDL) receptor in mediating VLDL-induced plasminogen activator inhibitor-1 (PAI-1) expression was studied in vitro. Cultured endothelial cells incubated with VLDL showed an increased secretion of PAI-1. This response to VLDL could be completely prevented by the receptor-associated protein (RAP) and partially blocked by rabbit polyclonal anti-VLDL receptor IgG. Furthermore, Chinese hamster ovary (CHO) control cells and cells overexpressing the VLDL receptor were transiently transfected with a PAI-1 promoter-reporter construct and incubated with VLDL. The PAI-1 promoter activity in response to VLDL was significantly higher in the VLDL receptor overexpressing cells compared to the control cells. Addition of RAP completely blocked the VLDL-activated PAI-1 transcription. Electromobility shift assay was performed to investigate whether the enhanced PAI-1 promoter activity seen in the VLDL receptor overexpressing cells in response to VLDL involved induction of the previously described VLDL-inducible factor(s) binding to the -675 to -653 region of the PAI-1 promoter. We found that the binding of the VLDL-inducible factor in VLDL receptor overexpressing cells was markedly enhanced by addition of VLDL as compared to control cells where no increased binding could be seen in response to VLDL. In summary, these results indicate that the VLDL receptor is a strong candidate for mediating VLDL effects on PAI-1 synthesis and secretion in cells expressing this receptor.

Animals↗

PubMed1999

Hereditary absence of complement C5 in adult mice influences Wallerian degeneration, but not retrograde responses, following injury to peripheral nerve.

We have examined the role of complement component 5 (C5) in peripheral nerve fiber degeneration and regeneration, as well as in glial and neuronal cell responses in the central nervous system (CNS). Adult congenic mice lacking C5 (C5(-)) and the corresponding normal strain (C5(+)) were used. Macrophage recruitment as well as axonal and myelin sheath elimination were delayed from 1 to 21 days postinjury in C5(-) mice compared to the C5(+) group after sciatic nerve crush. Despite this, recovery of motor function was not delayed. In the CNS, microglial cells and astrocytes responded in the same way from 3 to 21 days after sciatic nerve injury in C5(-) and C5(+) mice, and the extent of neuron death following hypoglossal nerve avulsion was the same in both groups. These findings suggest that C5 and/or its derivatives play an important role in initiating the recruitment of macrophages to the injured nerve and, probably indirectly, in early remyelination of regenerating axons, but does not influence the longterm functional restoration or axotomy-induced nerve cell death. C5-derived molecules do not appear to participate in central glial cell responses to peripheral nerve injury. These findings elucidate new aspects on the functional role of the complement system in the peripheral nervous system following peripheral nerve injury.

Animals↗

PubMed1999

A functional polymorphism in the apolipoprotein B promoter that influences the level of plasma low density lipoprotein.

Apolipoprotein (apo) B is the structural protein moiety of plasma low density lipoprotein (LDL), an important risk factor for coronary heart disease (CHD). There is evidence that the rate of synthesis of apoB-containing lipoproteins may play an important role in the regulation of plasma LDL levels. However, it is generally thought that transcriptional regulation of the apoB gene is not a significant determinant of the synthesis of apoB-containing lipoproteins, and by inference, of the regulation of the plasma LDL concentration. Here we report the discovery of a common polymorphism in the promoter region of the apoB gene, a C to T substitution at position -516. The -516T allele is associated with an increase in the basal transcription of the apoB gene (+41%, P < 0.05) in vitro in transfected HepG2 cells. Healthy middle-aged men who are homozygous for the -516T allele have 12% higher plasma LDL cholesterol levels than healthy homozygotes for the -516C allele (P < 0.05). The frequency of the -516T allele is significantly higher in young postinfarction patients (0.38) than in population-based controls (0.30) when the comparison is restricted to subjects without severe hypercholesterolemia who are homozygous for the apoE3 allele (P < 0.05). It is concluded that variation in the rate of transcription of the apoB gene can affect plasma LDL levels and influences the risk of CHD in middle-aged men.

Adult↗

PubMed1998

Bundle-branch block in a general male population: the study of men born 1913.

BACKGROUND: Interest in bundle-branch block has focused primarily on its role as a predictor of mortality and coexisting cardiovascular diseases. Previous studies of prevalence, correlation to cardiovascular disease, and mortality have produced conflicting results. METHODS AND RESULTS: We studied a random-sampled population of 855 men who were 50 years old in 1963 and followed them up for 30 years with repeated examinations. Men who developed bundle-branch block were studied with regard to cumulative incidence, relationship with cardiovascular disease/risk factors, and survival. The prevalence of bundle-branch block increases from 1% at age 50 years to 17% at age 80 years, resulting in a cumulative incidence of 18%. No significant relationship with ischemic heart disease or mortality was found. Men who would develop bundle-branch block had a bigger heart volume at age 50 years and developed diabetes mellitus and congestive heart disease during follow-up more often than control subjects. CONCLUSIONS: Bundle-branch block correlates strongly to age and is common in elderly men. Our results support the theory that bundle-branch block is a marker of a slowly progressing degenerative disease that also affects the myocardium.

Age Factors↗

PubMed1998

Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals.

High plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity, and both PAI-1 and obesity are risk factors for cardiovascular disease. To study the mechanisms underlying increased PAI-1 levels in obese individuals, gene expression and secretion of PAI-1 were measured in human abdominal subcutaneous adipose tissue. A total of 32 obese, otherwise healthy subjects and 10 never-obese healthy subjects with a body mass index (BMI) of 42.6 +/- 1.2 and 24.3 +/- 1.9 kg/m2 (mean +/- SEM), respectively, were investigated. Plasma PAI-1 activity, adipose tissue PAI-1 secretion and adipocyte PAI-1 mRNA levels were increased seven-fold (p < 0.0001), sixfold (p < 0.0001) and twofold (p < 0.05), respectively, in the obese group. There were clear associations between adipose tissue secretion of PAI-1 and PAI-1 mRNA levels on the one hand and fat cell volume on the other (r = 0.68, p < 0.0001 and r = 0.51, p < 0.01, respectively, in the obese group). PAI-1 mRNA levels were also related to the amount of PAI-1 secreted among obese individuals (r = 0.31, p = 0.09). It is concluded that adipose tissue secretes significant amounts of PAI-1, that PAI-1 secretion from adipose tissue is increased in obesity, and that PAI-1 secretion is related to the lipid content and cell volume of fat cells. Plasma PAI-1 activity is elevated in obesity, at least in part due to increased gene expression in adipocytes, which, in turn, enhances PAI-1 secretion from adipose tissue.

Adipose Tissue↗

PubMed1998

Lifelong ethanol consumption and loss of locus coeruleus neurons in AA and ANA rats.

The effects of lifelong ethanol exposure and aging on the morphology of the locus coeruleus (LC) were studied in the AA (Alko, Alcohol) and ANA (Alko, Nonalcohol) rats of both sexes. The ethanol-consuming (EtOH) rats were given 12% (v/v) ethanol as the only drinking fluid from 4 to 22 months of age, whereas the young (3-month-old) and aged (24-month-old) controls had only water available. The total LC neuron numbers were obtained by using the unbiased disector method. In the AA line, as we have previously reported. the EtOH female and male rats displayed a 26-30% loss of LC neurons compared with the controls. In the ANA line, the EtOH females had 30% fewer LC neurons than the controls (EtOH 1579 +/- 377 vs. controls 2264 +/- 269, ANOVA p < 0.01), whereas the EtOH males showed no neuron loss compared to the controls (EtOH 1848 +/- 525 vs. controls 2216 +/- 152, ANOVA NS). However, taking into account (sex by line ANCOVA) the markedly higher ethanol intake of the female rats in both lines, no gender or line differences in the ethanol-induced LC degeneration were detected. Neither was there any difference in LC neuron numbers between the young and old control rats of either line of rats. In conclusion, chronic alcohol consumption, not aging per se, damages the LC neurons in experimental animals.

Acetaldehyde↗

PubMed1998

Susceptibility in utero and upon neonatal exposure.

Important determinants or principles in developmental toxicology are: (1) genotype; (2) developmental stage when an insult is hitting; (3) mechanisms of action; (4) pharmacokinetics of the drug in the mother, conceptus and the neonate; (5) the manifestations of embryo/foeto- and neonatal toxicity such as death, malformations, growth inhibition and functional disturbances; and (6) dose-effect and dose-response relationships. The present paper will give a broad review of some important developmental events and sensitivity periods, such as the preimplantation period, the period of gastrulation, organogenesis and placental formation, the foetal and neonatal period during which xenobiotics can cause perturbation in the normal development. Mostly pharmaceuticals are used as examples due to their often well documented effects and sometimes known sensitivity periods. For the postnatal period, some neurotoxic pesticides and environmental pollutants, known to affect adult behaviour in experimental animals after perinatal exposure, are given as examples.

Abnormalities, Drug-Induced↗

PubMed1998

Effects of spinal cord stimulation on coronary blood flow velocity.

BACKGROUND: Spinal cord stimulation (SCS) has been used in the treatment of severe angina pectoris since the 1980s. Several studies have shown both an antianginal and an anti-ischaemic effect. There are several theories about the mechanism behind the anti-ischaemic effect of SCS, including the possibility that it is dependent on an increase in coronary flow velocity. OBJECTIVE: To determine if there were effects of SCS on coronary flow velocity during cardiac stress. METHOD: Eight patients with severe anginal pain secondary to coronary artery disease who had been implanted with an SCS device were included in the study. In addition, four patients with syndrome X were examined. If possible, a Doppler guidewire was placed in the vessel corresponding to the ischaemic area revealed on a prior myocardial scintigram. A temporary pacemaker electrode was placed in the right atrium. Atrial pacing started at 80 beats/min and increased by 10 beats/min every 2 min until the patient experienced moderate angina; the pacing frequency was then maintained at the same level. After 2 min of pacing at this frequency, SCS treatment commenced; after a further 5 min, pacing was stopped. Throughout the procedure, coronary flow velocity, assessed as average peak velocity (APV), was monitored continually. RESULTS: APV increased during pacing in all the patients with coronary artery disease (mean increase 53%; P < 0.02). There were no significant changes in APV during maximum pacing frequency when stimulation was introduced. CONCLUSIONS: The results of this study do not support the theory that the anti-ischaemic effect of SCS is dependent on an increase in coronary flow velocity.

Angina Pectoris↗

PubMed1998

Diagnosis of acute myocardial infarction in patients with chronic right bundle-branch block using standard 12-lead electrocardiogram compared with dynamic vector cardiography.

The aim of the study was to evaluate standard 12-lead electrocardiogram (ECG) criteria and to compare them with dynamic vector cardiography in patients with chronic right bundle-branch block for diagnosing acute myocardial infarction. We used standard 12-lead ECGs recorded on admission and after 12-24 h and compared them with dynamic vector cardiography with trend analysis during the first 12 h. In patients with right bundle-branch block, ST segment changes occurred in the same way as for patients with narrow QRS complexes. By adding 4 h of continuous vector cardiographic monitoring we were able to identify patients with acute myocardial infarction with a high diagnostic accuracy.

Aged↗

PubMed1998

Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia.

Hypertriglyceridemia and impaired fibrinolytic function are linked to coronary heart disease and other atherothrombotic disorders. Triglyceride-rich lipoproteins may attenuate fibrinolysis by increasing the plasma levels of plasminogen activator inhibitor-1 (PAI-1). Furthermore, a common 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been indicated to influence plasma PAI-1 activity and to be involved in an allele-specific response to triglycerides. Herein we show by transfection assays that VLDLs induce transcription of the human PAI-1 promoter in endothelial cells. A VLDL response element (VLDLRE) is located to residues -672 to -657 in the promoter region by electromobility shift assay, methylation interference, and DNase I footprinting, and its activity is shown to be influenced by the common 4G/5G polymorphism located adjacent to and upstream of the binding site of a VLDL-inducible transcription factor. These findings may provide a molecular explanation to the link between VLDL and PAI-1 activity elevation in plasma and to the interaction between the 4G/5G polymorphism and plasma triglycerides.

Base Sequence↗

PubMed1998

Unsaturated fatty acids increase plasminogen activator inhibitor-1 expression in endothelial cells.

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 micromol/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.

Cells, Cultured↗