Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P:eroxisome proliferator-activated receptor-gamma (PPARgamma) is a novel nuclear receptor, which enhances insulin-mediated glucose uptake. Ligands to PPARgamma are currently used as therapy for type II diabetes. Using Western blot analysis, RNase protection assay, and immunostaining, we identified the presence of PPARgamma message and protein in cultured primary rat mesangial cells. Electrophoretic mobility of a labeled PPARgamma response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARgamma is functional in these cells. The addition of unlabeled PPRE efficiently competed away the PPARgamma-PPRE protein complex, confirming specificity of binding of the PPARgamma to the PPRE. PPARgamma ligands rosiglitazone (1 to 10 micromol/L) and troglitazone (1 to 10 micromol/L) inhibited platelet-derived growth factor-induced DNA synthesis, measured as bromodeoxyuridine incorporation (P<0.01). This inhibition was dose dependent. When administered in antidiabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 3 months (from 687.1 to 137.6 microgram urinary albumin/mg creatinine, P:<0.05) but did not affect hyperglycemia or blood pressure in this model. This treatment also decreased glomerular plasminogen activator inhibitor-1 (PAI-1) expression. These data suggest that PPARgamma activation may directly attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy, or by inhibiting PAI-1 expression. PAI-1 inhibits the activation of plasmin and matrix metalloproteinase, which degrade extracellular matrix in the glomerulus. Excess glomerular PAI-1 allows the accumulation of extracellular matrix, leading to glomerulosclerosis. These results have therapeutic implications for diabetic nephropathy as well as for proliferative mesangial diseases of the kidney.
Hypertension 2001 Feb
PMID:Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells. 1123 Mar 63

Remodeling of blood vessels underlies the pathogenesis of major cardiovascular disorders, including atherosclerosis, restenosis, and hypertension. Because remodeling of arteries is highly dependent on degradation of the extracellular matrix, which enables cells to migrate and proliferate, there is intense interest in the regulation and the roles of matrix metalloproteinases (MMPs) and the plasminogen activator-plasmin (PA-P) systems in vessel remodeling. Factors that promote vessel remodeling have been shown to be important in upregulating the activities of both proteolytic systems and include chronic changes in hemodynamics, vessel injury, cytokines involved in inflammation, and elevations in reactive oxygen species. The two proteolytic systems utilize common transcription factors to activate their respective genes and are frequently coexpressed in remodeling and atherosclerotic arteries. In this review, we discuss the effects of activating the MMP and PA-P systems on processes involved in vascular remodeling, factors regulating their expression and activation, their roles in restenosis, and the development and progression of atherosclerosis, as well as the ability of currently available inhibitors to prevent unfavorable remodeling and atherosclerosis.
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PMID:Metalloproteinases and plasminogen activators in vessel remodeling. 1459 65

The importance of obtaining insight in the structure/function relationship in the serpin plasminogen activator inhibitor type-1 can be understood from the major role PAI-1 plays in different (patho)physiological processes, mainly because of its involvement in the plasminogen/plasmin system. Moreover, during the past years, studies indicated a contribution of PAI-1 to the development of cardiovascular disease in common syndromes such as atherosclerosis, diabetes and hypertension. Furthermore, PAI-1 also inhibits u-PA, attributing a role in phenomena such as cell migration and tissue remodelling. Considering the role of PAI-1 in such various pathogenic path-ways, detailed insight into the structure/function relationship in PAI-1 might provide a means of interfering with a given pathological situation without disturbing other physiological processes. Therefore, since the discovery of PAI-1 and the cloning of its cDNA 20 years ago, over 600 PAI-1 variants have been constructed, elucidating the most important structural features of PAI-1. This review gives an overview of the contribution of the different PAI-1 variants to the understanding of the structure/function relationship in PAI-1, based on the different functional features of PAI-1.
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PMID:The story of the serpin plasminogen activator inhibitor 1: is there any need for another mutant? 1554 16

Tissue plasminogen activator (tPA) is the predominant plasminogen activator present in the vascular and nervous systems. Prior studies of the two have emphasized different tPA sources; respectively, endothelium and neurons. A closer relationship is now suggested by evidence that the peripheral sympathetic nervous system synthesizes and infuses enzymatically active tPA into small artery walls and the microcirculation. TPA may thus be the only known neural product able to effect degradation of the artery wall extracellular matrix. This brief review considers historical and current indications for the existence of such an autonomically controlled system and some physiologic implications. Immunohistochemical tPA expression in small arteries and arterioles is more prominent in the outer wall sympathetic axon plexus than in endothelium. Its presence in nerve filaments beneath the seldom-studied adventitia was obscured in earlier localizations. The systemic impact of a neural distribution is suggested by a 60% reduction of blood tPA activity after chemical sympathectomy. TPA-bearing axons extend outward from ganglion neuron cell bodies to reach even thin-walled vasa vasora and uveal microvessels. Ganglion cell bodies synthesize and package tPA in vesicles for the long axoplasmic transport. Densely innervated intact vessels release much greater amounts of tPA in vitro than do larger vessels, indicating a high neuron tPA production capacity and a large storage reservoir available within axon networks. The influence of an autonomically controlled plasmin production within small artery walls on regulation of blood pressure and capillary perfusion awaits further investigation. Its possible role in the pathogenesis of vessel wall matrix degradations in aging, hypertension, and diabetes may also merit further consideration.
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PMID:Distribution of sympathetic tissue plasminogen activator (tPA) to a distant microvasculature. 1567 11

The aim of the paper was to determine concentrations of plasmin-alpha2 antiplasmin complexes (PAP) and D-dimers in blood of patients suffering from acute coronary syndromes without ST segment elevation. 78 patients, including 37 females and 41 males, aged 41-79 years (mean age 63.2) were included in the study. Concentrations of PAP were determined by immmunoenzymatic method using Enzygnost PAP micro kit and concentrations of D-dimers using Dade Berling Enzygnost D-Dimer micro kit. Statistically significant, higher concentrations of PAP and D-dimers, indicating increased fibrinolytic activity of blood, were observed in patients with acute coronary syndrome than in the control group. Significantly higher concentrations of D-dimers were found in the group of patients above the age of 50, when compared with younger patients. Lower D-dimers levels were observed in smokers. Gender, coexisting hypercholesterolaemia, arterial hypertension and diabetes had no impact on concentrations of PAP and D-dimers in blood of patients suffering from acute coronary syndrome without ST segment elevation.
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PMID:[Fibrinolysis parameters: plasmin-alpha2 antiplasmin complexes (PAP) and D-dimers in acute coronary syndromes without ST segment elevation]. 1577 Nov 20

Recurrent stress is clinically associated with early onset hypertension and coronary artery disease. A mechanism linking emotion to pathogenic remodeling of the artery wall has not been identified. Stress stimulates acute regulated release of tissue plasminogen activator (t-PA) into the circulation, which is presently attributed to the vascular endothelium. Sympathetic neurons also synthesize t-PA and axonally transport it to the arterial smooth muscle. Unlike release by the endothelium, a stress-stimulated sympathetic discharge would potentially accelerate degradation of the wall matrix by plasmin. To assess whether sympathetic axons are the principal source of acute stress-induced arterial release of t-PA, we compared the output from small densely innervated and large sparsely innervated isolated artery segments before and after sympathetic stimulation, and after ablations. Following phenylephrine infusion densely-innervated microvessels in uveal eyecups were released over 60-fold greater amounts of active t-PA per milligram than the sparsely innervated aorta; and ten-fold more than carotid artery segments. Mesenteric artery release was 4.8-fold greater than release by the carotid artery. In vivo, uveal release of t-PA increased more than three-fold within one minute following superior cervical sympathetic ganglion electrical stimulation, and after phenylephrine, or nicotine infusions of the anterior chamber. Circulating levels of t-PA fell 70% following chemical sympathectomy. We propose that sympathetic nerves are the primary source of stress-induced release of t-PA into and from the densely innervated resistance arteries and arterioles, where dysregulated plasmin-induced proteolysis could damage the wall matrix.
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PMID:Stimulated release of tissue plasminogen activator from artery wall sympathetic nerves: implications for stress-associated wall damage. 1601 5

Kidney transplant recipients are prone to hypertension, dyslipidemia, and cardiovascular death. Hypertension is associated with hemostatic abnormalities. Thrombin activatable fibrinolysis inhibitor (TAFI) is a glycoprotein that links coagulation and fibrinolysis. The purpose of this study was to assess TAFI concentrations in renal transplant recipients in relation to blood pressure. Additionally, we evaluated thrombin activity (thrombin-antithrombin complex [TAT], prothrombin fragments 1+2 [F1+2]), thrombomodulin (TM), and the degree of plasmin generation (plasmin-antiplasmin complex [PAP]) using commercially available kits. The studies were performed on 86 renal allograft recipients (48 women, 38 men) at age range 26 to 73 years. The immunosuppressive regimen consisted of cyclosporine (CsA), prednisone, and azathioprine (n = 58) or mycophenolate mofetil (MMF; n = 28). All patients maintained sufficient and stable graft function, showing no clinical signs of rejection. In patients with hypertension (n = 68), we observed significantly higher concentrations of TAFI and of markers of thrombin generation (F1+2, TAT), and of thrombomodulin with significantly prolonged euglobulin clot lysis time (ECLT), which reflects overall fibrinolytic activity and lower fibrinolytic activity index (FAI). Both groups did not differ with respect to age, creatinine clearance, body mass index, time after transplantation, albumin, fibrinogen, and PAP. Diastolic blood pressure correlated significantly with TAFI concentrations, uric acid, and prednisone dose, whereas systolic blood pressure correlated with urea, uric acid, creatinine clearance, and MCV. Elevated TAFI concentrations and enhanced thrombin generation in hypertensive kidney transplant recipients may contribute to the hypofibrinolysis and progressive atherosclerosis in this population. Blood pressure was related to kidney function, maintenance prednisone dose, and TAFI concentration.
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PMID:Thrombin activatable fibrinolysis inhibitor in hypertensive kidney transplant recipients. 1650 76

Obesity is a common disorder and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity; the role of specific members of these families, however, remains to be determined.
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PMID:Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. 1717 99

We tested the hypothesis that selected prothrombotic biomarkers might be associated with early spontaneous coronary recanalization in patients with ST-segment elevation acute myocardial infarction (STEMI). We prospectively enrolled 123 patients with STEMI including 53 patients with spontaneous coronary recanalization (cases) and 70 patients with persistent occlusion (controls) at the time of emergent coronary angiography and before angioplasty. All had received aspirin and heparin. Blood samples were collected immediately before angioplasty to measure soluble P-selectin, circulating microparticles originating from platelets (PMPs), granulocytes (GMPs), endothelial cells (EMPs); tissue factor-associated MP (TF-MP); soluble platelet glycoprotein V (sGPV) and prothrombin F1 + 2; tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) and plasmin-antiplasmin (PAP). A sub-group of 70 patients (35 cases, 35 controls) was available for flow cytometry analysis of platelet P-selectin and activated GPIIb-IIIa. Baseline clinical characteristics did not differ between groups except for more frequent hypertension and dyslipidemia in controls. Platelet activation markers and PMP did not differ between the two groups. Controls had higher numbers of EMPs and GMPs compared to cases, but the difference was no longer significant when corrected for risk factors. Controls differed from cases by higher plasma levels of sGPV [64 (47-84) ng/ml vs. 53 (44-63) ng/ml] and PAP [114(65-225) ng/ml vs. 88 (51-147) ng/ml]. The difference persisted after adjustment for risks factors (p = 0.031 and 0.037, respectively). Persistent occlusion of the infarct related artery is associated with some markers related to higher thrombin (sGPV) and plasmin (PAP) production but is not associated with markers of platelet activation.
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PMID:Prothrombotic markers and early spontaneous recanalization in ST-segment elevation myocardial infarction. 1772 26

The plasma level of chromogranin A (CgA) is elevated in genetic hypertension. Conversely, the plasma level of the CgA peptide catestatin is diminished in individuals with established hypertension and those with a genetic risk of this disease. Resequencing of the human CHGA gene identified three naturally occurring variants of catestatin (Gly364Ser, Pro370Leu, and Arg374Gln) that exhibit different potencies in inhibiting catecholamine secretion. Here, we have examined whether there is any differential processing of the three CHGA variants to catestatin by the endoproteolytic enzyme plasmin. Plasmin digestion of the purified CgA proteins generated a stable biologically active 14-amino acid peptide (human CgA(360-373)) from the wild-type, Gly364Ser, and Arg374Gln proteins despite the disruption of the dibasic site (Arg(373)Arg(374)) in the Arg374Gln variant. Unexpectedly, the action of plasmin in generating the catestatin peptide from the Pro370Leu protein was less efficient. The efficiency of cleavage at the dibasic Arg(373) downward arrowArg(374) site in synthetic human CgA(360-380) was 3- to 4-fold less in Pro370Leu CgA, compared with the wild type. Circular dichroism of the synthetic CgA(352-372) suggested a difference in the amount of alpha-helix and beta-sheet between the wild-type and Pro370Leu CgA peptides. Because the Pro(370) residue is in the P4 position, the local secondary structure in the vicinity of the cleavage site may enforce the specificity or accessibility to plasmin. The less efficient proteolytic processing of the Pro370Leu protein by plasmin, coupled with the strong association of this variant with ethnicity, suggests that the Pro370Leu CHGA gene variant may contribute to the differential prevalence of cardiovascular disease across ethnic groups.
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PMID:Proteolytic cleavage of human chromogranin a containing naturally occurring catestatin variants: differential processing at catestatin region by plasmin. 1799 25


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