Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse is the most commonly used species for in vivo studies on angiogenesis related to tumor development. Yet, to the best of our knowledge, very few reports on the in vitro interaction of the angiogenic basic fibroblast growth factor (bFGF) with mouse endothelial cells are available. Three mouse endothelial cell lines originated from aorta (MAECs), brain capillaries (MBECs), and heart capillaries (MHECs) were characterized for endothelial phenotypic markers, in vivo tumorigenic activity, and the capacity to respond in vitro to bFGF. These cells express angiotensin-converting enzyme, acetylated LDL receptor, constitutive endothelial nitric oxide synthase, and vascular cell adhesion molecule-1 and bind Griffonia simplicifolia-I lectin. When injected subcutaneously in nude mice, MAECs induced the appearance of slow-growing vascular lesions reminiscent of epithelioid hemangioendothelioma, whereas MBEC xenografts grew rapidly, showing Kaposi's sarcoma-like morphological features. No lesions were induced by injection of MHECs. MAECs, MBECs, and MHECs expressed both low-affinity heparan sulfate bFGF-binding sites and high-affinity tyrosine kinase receptors (FGFRs) on their surfaces. In particular, MAECs expressed FGFR-2/bek mRNA, whereas microvascular MBECs and MHECs expressed FGFR-1/flg mRNA. Accordingly, bFGF induced a mitogenic response and the phosphorylation of extracellular signal-regulated kinase-2 in all the cell lines. In contrast, upregulation of urokinase-type plasminogen activator expression was observed in bFGF-treated microvascular MBECs and MHECs but not in MAECs. Also, bFGF-treated MBECs and MHECs but not MAECs invaded a three-dimensional fibrin gel and formed hollow, capillary-like structures. The relevance of the modifications of the fibrinolytic balance of mouse microvascular endothelium in bFGF-induced angiogenesis was validated in vivo by a gelatin-sponge assay in which the plasmin inhibitors tranexamic acid and epsilon-aminocaproic acid given to mice in the drinking water inhibited neovascularization induced by the growth factor. In conclusion, differences in response to bFGF exist between large-vessel MAECs and microvascular MBECs and MHECs. Both in vitro and in vivo data point to a role of the profibrinolytic phenotype induced by bFGF in microvascular endothelial cells during mouse angiogenesis. Our observations make these endothelial cell lines suitable for further studies on mouse endothelium during angiogenesis and in angioproliferative diseases.
 ...
PMID:Basic fibroblast growth factor-induced angiogenic phenotype in mouse endothelium. A study of aortic and microvascular endothelial cell lines. 910 63

Transforming growth factor-beta1 (TGF-beta1) is involved in different physiological and pathological processes, including atherogenesis. High plasma lipoprotein(a) (Lp(a)) concentration is an established independent risk factor that may interfere with the plasmin-mediated TGF-beta1 activation. Both Lp(a) and TGF-beta1 are thought to influence the expression of cellular adhesion molecules (CAMs), also involved in the process of atherogenesis. Whereas many studies confirmed the association between high plasma Lp(a) levels and coronary artery disease (CAD), conflicting results were obtained in different studies in which the changes of TGF-beta1 and CAM concentrations in CAD patients were investigated. The aim of this case-control study was to explore the association of circulating TGF-beta1, Lp(a) and CAMs (intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin) levels with the occurrence and severity of angiographically assessed coronary artery disease. Plasma TGF-beta1, Lp(a), ICAM-1, VCAM-1 and E-selectin concentrations were measured in 100 patients with angiographically assessed CAD and 100 healthy blood donors matched according to age and gender. Lp(a) and TGF-beta1 were significantly higher in patients than in healthy controls (p < 0.001 and p < 0.01, respectively), but no significant correlation between the TGF-beta1 and Lp(a) values was found. The CAM concentrations obtained in CAD patients did not differ significantly as compared with the corresponding values in the controls. None of the measured parameters were influenced by the severity of CAD.
 ...
PMID:Circulating transforming growth factor-beta1, lipoprotein(a) and cellular adhesion molecules in angiographically assessed coronary artery disease. 1294 May 14

Probucol [4,4'-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] was withdrawn from the United States market because it failed to inhibit atherosclerosis in human femoral arteries, yet the drug was shown subsequently to inhibit atherosclerosis in human carotid arteries, and probucol monosuccinate ester is presently being tested in a phase III clinical trial as an antiatherosclerotic compound based on its anti-inflammatory properties. Inflammatory macrophages are implicated in arterial remodeling associated with atherosclerosis, and probucol inhibits experimental atherosclerosis in part by decreasing macrophages in lesions. However, the impact of probucol on remodeling is unknown, although such knowledge could help explain why the drug's benefit on human atherosclerosis is controversial. We therefore examined the effect of probucol on remodeling of the common carotid artery in apolipoprotein E-deficient mice. We observed that during de novo atherosclerosis, plaque growth was fully compensated by expansive remodeling, such that lumen area was unaffected. Early lesions were composed almost entirely of macrophages, and their contribution to lesion area progressively decreased thereafter. Probucol significantly decreased plaque area, expression of vascular cell adhesion molecule-1, and proliferation of intimal cells, resulting in delayed macrophage accumulation in the vessel. Probucol also decreased the production and activity of matrix metalloproteinases-2 and -9, independent of the plasmin protease system, and this was associated with an inhibition of expansive remodeling, resulting in lumen loss. These studies show that probucol attenuates compensatory remodeling associated with de novo atherosclerosis, probably via its anti-inflammatory properties. Our findings suggest that lumen volume is not a suitable surrogate to assess the antiatherosclerotic activity of probucol and related drugs.
 ...
PMID:Probucol [4,4'-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] inhibits compensatory remodeling and promotes lumen loss associated with atherosclerosis in apolipoprotein E-deficient mice. 1729 60

We hypothesized that restenosis after coronary stenting is predicted by elevated levels of markers of thrombus formation and inflammation. Plasma levels of representative markers of inflammation, the thrombin and plasmin activation systems and adhesion molecules were measured in 59 patients with stable angina pectoris before, immediately after and 6 hours (h), 12 h, 24 h, one month and six months after elective stent implantation (radioactive phosphorus-32 stents/RSs/ n = 16, bare-metal stents/BMSs/ n = 43). All patients underwent clinical and angiographic follow-up (FUP) six months after stenting. RSs had significantly higher angiographic severity of restenosis than BMSs (47.1 +/- 20.1% vs. 27.6 +/- 22.0%, p = 0.003). Repeated measures ANOVA revealed significant differences between the BMS and RS groups as regards the increases in plasma levels of vascular cell adhesion molecule-1 (VCAM-1, p = 0.022), plasminogen activator inhibitor-1 (PAI-1, p = 0.047), tissue-type plasminogen activator (tPA, p = 0.047) and CD40 ligand (CD40L, p = 0.038). tPA levels tended to increase immediately after stenting in both groups, whereas the PAI-1 level one month after stenting was elevated significantly only in the RS group. In the RS group, the plasma levels of CD40L were increased at 24 h and six months after stenting, and the VCAM-1 level rose immediately after stenting and remained high during the FUP. Multivariate analysis on pooled laboratory data of both groups revealed elevated levels of VCAM-1 at 12 h and at six months as significant predictors of the severity of stent restenosis. In conclusion, the process of inflammation and thrombosis occurring after coronary interventions seems to be prolonged and enhanced in patients with high-grade restenosis at the follow up.
 ...
PMID:Time course of prothrombotic and proinflammatory substance release after intracoronary stent implantation. 1839 32

Proteinases have been implicated in the mobilization of haematopoietic progenitor cells (HPCs) from the bone marrow (BM). Here, we report the involvement of the plasminogen (Plg) system in the haematopoietic recovery following chemotherapy. By using gene-deficient mice, we found that plasmin and its activators tPA and uPA play a role in the haematopoietic recovery upon delivery of the cytotoxic agent 5-fluoro-uracil (5-FU). The impaired haematopoietic recovery of Plg-deficient (Plg(-/-)) mice after 5-FU was not rescued by depletion of fibrinogen, indicating that it was not due to defective fibrinolysis. Instead, loss of Plg impaired breakdown of fibronectin, VCAM-1 and laminin-BM matrix proteins involved in adhesion of HPCs to their BM microenvironment and in transendothelial migration of HPCs. These findings provide novel insights in how plasmin regulates haematopoietic recovery upon cytotoxic myeloablation.
 ...
PMID:Fibrinolysis-independent role of plasmin and its activators in the haematopoietic recovery after myeloablation. 1921 Feb 87

Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, d-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.
 ...
PMID:A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD. 3130 Apr 20