SummaryType 2 diabetic patients are known to frequently have a high insulin level and were recently described as having high plasminogen activator inhibitor (PAI) activity, compared to normal controls. As we have shown in several clinical conditions (normal subjects, obese patients, angina pectoris patients) that plasma PAI activity was linked with plasma insulin, we have studied in 38 type 2 diabetic patients the relationship between PAI activity, insulin and other parameters. Patients showed higher level of PAI activity, as well as plasma glucose, insulin, triglyceride, cholesterol and Apolipoprotein B levels than normal controls; highest values were observed with diabetic patients also affected by coronary artery disease. A significant correlation was found between PAI activity and insulin (r = 0.60, p <0.001), body mass index (r = 0.32, p <0.05) and Apolipoprotein B (r = 0.33, p <0.05). The two latter correlations disappeared after adjustment for insulin.These results are in agreement with our previous report showing an in vitro effect of insulin on the synthesis of PAI by a hepatocellular cell line. Hyperinsulinemia presented by type 2 diabetic patients may increase the hepatic synthesis of PAI, inducing an hypofibrinolysis, which could play a role in the development of the vascular complications.Attempts to reduce hyperinsulinemia could have a favorable effect by lowering PAI activity.
SummarySecretion of plasminogen activator inhibitor 1 (PAI-1) by cultures of human umbilical vein endothelial cells and human hepatocellular cell line Hep G2 was evaluated after insulin stimulation. The secretion of PAI-1 antigen and activity was measured in the conditioned medium and the cellular extracts after incubation of confluent cultures with 1% serum medium for 24 hours.Insulin induced a dose dependent increase of the PAI-1 secretion by Hep G2 cell line. At 10-8 M a two fold increase of PAI-1 antigen and activity were observed whereas a2 antiplasmin and fibrinogen were not significantly modified. No effect of insulin was observed on PAI-1 antigen and PAI activity production by human endothelial cells whereas endotoxin resulted in a two fold increase in PAI-1 secretion. In recent clinical studies we have demonstrated that the level of plasma insulin correlated with that of PAI-1. Thus we hypothesize that hepatocytes represent a physiological source of plasma PAI-1 which is modulated by plasma insulin level.
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.
Gray platelet syndrome (GPS) is a rare recessive disorder caused by variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet alpha-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4-lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.
SummaryPlasminogen activator inhibitor type 1 (PAI-1), a risk marker of atherosclerosis, is highly expressed in adipose tissue from obese subjects. PAI-1 is also considered as an acute phase protein. Recently, adipose tissue has been described as a source of inflammatory cytokines. Therefore, our aim was to study the relationships between PAI-1, and IL-6, TNF, TNF receptors (TNFRSF1s) and TGFβ1, in plasma and adipose tissue from obese (n = 60) and lean (n = 28) subjects. Study has been extended to plasminogen activators (t-PA and u-PA).Compared to lean subjects, obese subjects exhibited higher plasma levels of all the studied parameters (except for TGFβ1) whereas in adipose tissue only PAI-1, t-PA and TGFβ1 antigen levels differed. In the obese population, plasma PAI-1 levels were weakly associated with circulating TNF, and this relationship disappeared after adjustment for plasma t-PA. Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFβ1, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability. TNF and IL-6 were the main contributors to t-PA variability in plasma and in adipose tissue, respectively.Our results argue on the relevance of TNFRSF1s in the regulation of PAI-1 expression by adipose tissue. Association between t-PA, which is mainly produced by endothelial cells, and IL-6 or TNF suggest that inflammation might be involved in angiogenesis in adipose tissue.Abbreviations: act: activity; ag: antigen; BMI: Body mass index; IL-6: Interleukin-6; PAI-1: plasminogen activator inhibitor type 1; TGFβ1: Transforming Growth Factor beta 1; TNF: Tumor Necrosis Factor alpha; TNFRSF1A and 1B: Tumor Necrosis Factor receptor superfamilly 1A and 1B (TNFRI and II respectively); t-PA: tissue type plasminogen activator; u-PA: urokinase type plasminogen activator
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