Biomedical subjects
P Morange
Publications and source records attributed to P Morange.
Combined segregation-linkage analysis of plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels with TAFI gene polymorphisms.
By decreasing plasminogen binding to fibrin surface, the thrombin activatable fibrinolysis inhibitor (TAFI) has been hypothesized to constitute an early marker for atherothrombotic diseases. Previous studies have shown that plasma TAFI levels exhibit a high interindividual variability that is only poorly explained by lifestyle factors. Several polymorphisms of the TAFI gene have been described, and a combination of a C+1542G substitution in the 3' untranslated region and an Ala147Thr amino acid change has been shown to explain 60% of TAFI variability in a sample of unrelated individuals. A segregation-linkage analysis was performed to determine whether these polymorphisms are directly involved in the genetic regulation of TAFI levels, or whether they are only markers in linkage disequilibrium (LD) with unmeasured TAFI-linked quantitative trait loci (QTLs). The sample consisted of 97 healthy nuclear families from the Stanislas Cohort. The C+1542G and Ala147Thr polymorphisms were in complete negative LD, with minor allele frequencies of 0.27 and 0.28, respectively. Results of the segregation-linkage analysis provided evidence of two TAFI-linked QTLs in LD with the two measured polymorphisms, which would explain 78% of the TAFI variance, as compared with 55% explained by the C+1542G and the Ala147Thr polymorphisms combined. The two putative QTLs would have minor allele frequencies of 0.45 and 0.32, respectively. The hypothesis that one of the measured polymorphisms is one of the QTLs was rejected. The putative QTLs also did not seem compatible with the other TAFI gene polymorphisms that we have previously described. More extensive sequencing of the TAFI gene is necessary to identify the functional variants.
Adipose tissue expression of gelatinases in mouse models of obesity.
Following the observation by Brown et al. (Am J Physiol 1997; 272: C937-49) that primary rat adipocytes in culture secrete gelatinase A (MMP-2), we have evaluated gelatinase expression in adipose tissue with the use of mouse models of obesity. Wild-type mice were kept on a standard fat diet (SFD) or on a high fat diet (42% fat, HFD) and- genetically obese db/db mice were kept on SFD; gonadal and subcutaneous fat pads were removed and analysed ex vivo. These studies revealed that: 1) the HFD induced adipocyte hypertrophy; 2) after 32 weeks, significantly higher levels of 70 kDa (p <0.05) and 65 kDa proMMP-2 (p <0.01) were observed in extracts of gonadal fat pads of mice on HFD; 3) the contribution of active MMP-2 to the total level was comparable in SFD and HFD groups (20 to 30%); and 4) gelatinase B (MMP-9) was not consistently detected. These findings were confirmed by gelatin zymography and by mRNA determination using competitive RT-PCR. The presence of MMP-2 in the adipose tissue was confirmed immunologically and its localization in adipocytes revealed by immunogold electron microscopy. The potential functional role of MMP-2 in adipose tissue remains to be determined.
Acquired inhibitor of thrombin associated with an ulcerative colitis.
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Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity.
In adipose tissue from both obese mice and humans, plasminogen activator inhibitor 1 (PAI-1) expression has been reported to be upregulated to levels of increased plasma PAI-1. This elevated expression has been shown to be partly controlled by tumor necrosis factor (TNF)-alpha in mice. In humans, increased PAI-1 expression is associated with insulin resistance characterized by visceral fat accumulation. Therefore, the aim of this study was to investigate the expression pattern of PAI-1 and TNF-alpha (antigen and mRNA) in visceral human adipose fat in comparison with subcutaneous (SC) fat. Because transforming growth factor (TGF)-beta1 is a potent inducer of PAI-1 synthesis and has been shown to influence adipocyte metabolism, this work was extended to TGF-beta1 quantification. A total of 32 obese individuals (BMI 42 +/- 6.8 kg/m2) were investigated. Freshly collected visceral adipose tissue did not exhibit a higher content of PAI-1 or TGF-beta1 than did SC tissue. Although most of the TNF-alpha values were at the detection limit of the methods, TNF-alpha antigen was 3-fold higher and TNF-alpha mRNA was 1.2-fold higher in visceral fat. The levels of tissue TGF-beta1 antigen correlated well with those of PAI-1 antigen, regardless of the fat depot studied (SC tissue: n = 21, r = 0.72, P = 0.0006; visceral tissue: n = 20, r = 0.49, P < 0.03), and they were both significantly associated with BMI. Conversely, no relationship was observed between the levels of TNF-alpha and PAI-1 or TNF-alpha and BMI. Tissue PAI-1 levels were also significantly correlated with those of circulating PAI-1. These results describe, in severe obesity, a proportional increase in tissue PAI-1 and TGF-beta1 in visceral and SC tissues. This increased PAI-1 expression could be the result of tissue cytokine disturbances, such as elevated TGF-beta1 expression.
Fibrinolytic function and coronary risk.
Plasminogen activation potential in the blood is controlled by an equilibrium between plasminogen activators, mainly tissue-type plasminogen activator (t-PA), and inhibitors, mainly plasminogen activator inhibitor (PAI)-1. In cardiovascular practice, imbalance of this fibrinolytic potential is encountered primarily in the insulin-resistance syndrome. This syndrome leads to increased plasma PAI-1 and t-PA antigen levels (reflecting inactive t-PA/PAI-1 complexes) with a consequent decrease in fibrinolytic activity. Increased plasma PAI-1 and t-PA antigen both are predictive of myocardial infarction. The prognostic value of PAI-1 disappears after adjustments for insulin resistance markers, whereas the prognostic value of t-PA antigen disappears after simultaneous adjustments for insulin resistance and inflammation markers, suggesting an additive role of inflammation in inducing plasma fibrinolytic markers. Recently the production of PAI-1 by adipose tissue, in particular by tissue from the omentum, has been shown. PAI-1 produced in this way could be an important contributor to the elevated plasma PAI-1 levels observed in insulin-resistant patients. These results support the notion that PAI-1 may be a link between obesity, insulin resistance, and cardiovascular disease. Genetic control of PAI-1 expression has also been shown, involving a -675 4G/5G polymorphism, the 4G/4G genotype being associated with higher plasma PAI-1 levels; its proper influence on the development of myocardial infarction is still debated.
Catastrophic arterial reactivity during primary antiphospholipid syndrome--a case report.
Arterial reactivity leading to acute thrombosis at the site of a needle stick injury has never been described during antiphospholipid syndrome. The authors report a case characterized by a succession of thrombotic events occurring during or immediately after arterial angiographies or arterial surgery, in which catastrophic arterial reactivity can be strongly suspected. In this particular patient, it can be postulated that damage to the endothelial cells of the vessels injured during manipulation may have precipitated or aggravated the preexisting susceptibility to thrombosis.
Fibrinogen, obesity and insulin resistance.
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Activation of plasminogen activator inhibitor-1 synthesis by phorbol esters in human promyelocyte HL-60--roles of PCKbeta and MAPK p42.
HL-60 cells treated by PMA develop the monocyte adherent phenotype and synthesize plasminogen activator inhibitor type-1 (PAI-1). We focused our study on the identification of the PMA-activated protein kinase C (PKC) isoform and its downstream transduction pathway activating PAI-1 synthesis. Acquisition of the monocytic phenotype was evidenced by cell adherence (90-95%) and a sharp increase of CD 36 and receptor for urokinase plasminogen activator (uPAR) surface expression. Ro 31-8220, a specific inhibitor of PKC, prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion. To identify the PKC isoform, we took advantage of the HL-525 cell line, an HL-60 cell variant deficient in PKCbeta gene expression. This defect prevents PMA to induce the differentiation process. HL-525 stimulated by PMA did not synthesize PAI-1 nor become adherent. However, in HL-525 cells either pretreated by retinoic acid that reinduces PKCbeta gene expression or transfected with PKCbeta cDNA, PMA significantly activated PAI-1 synthesis and adhesion of cells. Immunoblotting of active Mitogen Activated Protein Kinase (MAPK) p42/p44 in HL-60 cells showed a preferential and sustained activation of the p42 isoform by PMA over the p44 isoform. Ro 31-8220 significantly attenuated this activation. PD 098059 and U0126, both highly specific MEK inhibitors, efficiently prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion whereas SB203580, a specific inhibitor of stress-activated MAPK p38, did not. Results obtained from HL-60 and HL-525 cells indicate that the PMA-activated transduction pathway of uPAR expression involves a PKC isoform other than PKCbeta. In conclusion, we propose that the pathway PKCbeta-MEK-MAPK p42 is a potential linear route for PAI-1 synthesis leading to morphological changes and adherence linked to PMA-induced differentiation in HL-60 cells.
Relationship of plasminogen activator inhibitor-1 levels following thrombolytic therapy with rt-PA as compared to streptokinase and patency of infarct related coronary artery.
BACKGROUND: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries. METHODS AND RESULTS: Fifty five consecutive patients with acute MI were randomized to streptokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5+/-1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p<0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p<0.002, p<0.04 and p<0.05 respectively). The same tendency was observed in the t-PA group without reaching significance. CONCLUSIONS: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.
Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: the BIGPRO1 Study. Biguanides and the Prevention of the Risk of Obesity.
OBJECTIVE: Insulin resistance is associated with hypofibrinolysis. Metformin has been shown to improve insulin sensitivity and fibrinolysis. Its action on fibrinolysis and the von Willebrand factor was evaluated in the Biguanides and the Prevention of the Risk of Obesity (BIGPRO)1 trial in nondiabetic men (n = 151) and women (n = 306) aged between 34 and 65 years with a central fat distribution and a mean BMI of 32.5 kg/m2. RESEARCH DESIGN AND METHODS: The subjects were randomly allocated to a 1-year treatment with metformin (850 mg b.i.d.) or placebo, in addition to diet and exercise recommendations. RESULTS: Plasminogen activator inhibitor 1 (PAI-1) activity and antigen decreased significantly but similarly by 30 and 40%, respectively, in both the placebo and the metformin groups. This decrease occurred mainly in subjects who lost weight. Metformin did not have any significant additional effect on PAI-1. In contrast to the results for PAI-1, there was a significantly greater decrease in tissue-type plasminogen activator (tPA) antigen in the metformin than in the placebo group (mean+/-SD: -1.1+/-3.1 vs. 0.2+/-3.2 ng/ml, P < 0.02). The von Willebrand factor (vWF) also decreased significantly more in the metformin group (-0.17+/-0.42 vs. -0.05+/-0.38 U/I, P < 0.02). CONCLUSIONS: Weight loss was the main factor associated with the decrease in PAI-1, in accordance with the recent demonstration of production of PAI-1 by adipocytes. Metformin had a significant effect on two factors, tPA antigen and vWF, mainly secreted by the endothelial cells, which suggests an effect of the drug on the production or the metabolism of these two hemostatic proteins.
Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease.
Plasminogen activator inhibitor type 1 (PAI-1) contributes to the pathogenesis of atherothrombosis. Its plasma level is strongly correlated with parameters that define the insulin resistance syndrome, in particular with BMI and visceral accumulation of body fat, suggesting that PAI-1 may be an adipose tissue-derived circulating peptide. The present study was designed to investigate PAI-1 expression by human adipose tissue and its different cellular fractions. Special interest has been paid to the amount of PAI-1 antigen produced by omental versus subcutaneous fat. PAI-1 protein detected by immunolocalization was present at the stromal and adipocyte levels. PAI-1 mRNA was detected in stromal vascular cells freshly isolated and under culture conditions. It was also detected in whole adipose tissue and adipocyte fraction under culture conditions. The mRNA signal from the adipocyte fraction was detected as early as 2 h of incubation. The increase in PAI-1 mRNA was followed by an increase in PAI-1 antigen in the conditioned medium that was suppressed by treatment with cycloheximide. Transforming growth factor-beta1 significantly increased PAI-1 antigen production by the adipocyte fraction, whereas tumor necrosis factor-alpha did not have any effect. Interestingly, after 5 h of incubation, omental tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, whereas similar production of leptin by the two territories was observed. These results strongly suggest that human adipose tissue, in particular visceral tissue, can be an important contributor to the elevated plasma PAI-1 levels observed in central obesity.
Resistance to activated protein C--diagnostic strategy in a laboratory of haemostasis.
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Fat cell function and fibrinolysis.
Plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and may be the principal regulator of plasminogen activation in vivo. PAI-1 levels are elevated in insulin-resistant subjects and are associated with an increased risk of atherothrombosis. After adjustment for metabolic parameters, increased PAI-1 levels were no longer considered as a cardiovascular risk factor. The mechanisms underlying the strong association between PAI-1 levels and the metabolic disturbances found in insulin resistance are still not understood. Several studies have suggested that visceral adipose tissue may be a major source of PAl-1. Accordingly, adipose tissue PAI-1 production particularly that from visceral fat, was found to be elevated in obese human subjects. Within human adipose tissue, stromal cells appear to be the main cells involved in PAI-1 synthesis. This review discusses the potential mechanisms linking adipose tissue to plasma PAI-1 levels such as the intervention of cytokines (TNFalpha and TGFbeta), free fatty acids and hormones (insulin and glucocorticoids). Moreover alteration of adipose tissue cellular composition induced by the modulation of PAI-1 expression opens a novel field of interest.