Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the source of the increased release of tissue plasminogen activator (t-PA) into the circulation that occurs during natural aging. Both the basal release and the acute stress-associated release induced by sympathetic stimulations are greater in older subjects. It is widely assumed that the source of these increases is vascular endothelium. However, the sympathetic neurons that densely innervate resistance vessel walls were recently shown to synthesize and transport active t-PA to axon terminals in vascular smooth muscle, suggesting an alternative source. These fine t-PA-bearing axons lie in the seldom-studied deep adventitia of vessel walls, where they are less visible than endothelium in tissue sections. Using Northern blot analysis, we observed that t-PAmRNA synthesis is increased 54% in the ganglion parent neuron cell bodies that innervate aged vessels. The t-PA release from isolated, aged ganglia in cultures was twofold greater than that from younger controls. In addition, aged whole-artery explants showed a 20% greater basal and a 50% greater acute release of stored t-PA in vitro. In vivo levels of active t-PA were 33% greater in the blood and 40% greater in the aqueous humor. These results are consistent with an increased infusion of the active t-PA protease from sympathetic axon terminals into the vessel wall extracellular matrix and the blood during natural aging, in addition to the basal endothelial release. We suggest that the cumulative impact of an accelerated plasmin production and matrix degradation within vessel walls, especially during repetitive stress, may play an unrecognized role in the pathogenesis of vascular aging. The possibility that increased sympathetic nervous system plasminogenesis influences the aging process in nonvascular tissues also deserves further investigation.
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PMID:Enhanced tissue plasminogen activator synthesis by the sympathetic neurons that innervate aging vessels. 1254 13

The capacity of vascular endothelium to locally release tissue-type plasminogen activator (t-PA) represents an important endogenous defence mechanism against intravascular fibrin deposition and thrombosis. We determined the influence of chronic and acute oestrogen administration on endothelial t-PA release in postmenopausal women. Sixty-three healthy postmenopausal women were studied: 31 non-users (age 58 +/- 1 years) and 32 users of hormone replacement therapy, including oestrogen alone (ORT: 62 +/- 2 years; n = 15) and in combination with progesterone (HRT: 57 +/- 1 years; n = 17). Net endothelial t-PA release was determined in vivo, in response to intrabrachial infusions of bradykinin and sodium nitroprusside. To examine the acute effects of oestrogen on endothelial t-PA release, bradykinin and sodium nitroprusside dose-response curves were repeated in the presence of 17 beta-oestradiol in 20 of the 31 non-users. Net endothelial release of t-PA was ~30 % higher (P < 0.01) in women taking ORT (from 2.0 +/- 1.0 to 83.6 +/- 9.2 ng (100 ml tissue)-1 min-1) compared with those taking HRT (from 1.4 +/- 0.4 to 63.5 +/- 5.6 ng (100 ml tissue)-1 min-1) and those not taking supplementation (1.0 +/- 0.7 to 63.0 +/- 4.7 ng (100 ml tissue)-1 min-1). Intra-arterial infusion of 17 beta-oestradiol significantly potentiated bradykinin-induced t-PA release. Net endothelial release of t-PA was approximately 45 % higher (P < 0.01) after (from 1.0 +/- 0.8 to 87.4 +/- 9.9 ng (100 ml tissue)-1 min-1) versus before (1.2 +/- 0.6 to 60.8 +/- 5.6 ng (100 ml tissue)-1 min-1) acute 17 beta-oestradiol administration. Our results suggest that oestrogen has a direct modulatory effect on the capacity of the endothelium to release t-PA in healthy postmenopausal women. However, progesterone appears to oppose the favourable influence of oestrogen on endothelial fibrinolytic capacity.
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PMID:Acute and chronic effects of oestrogen on endothelial tissue-type plasminogen activator release in postmenopausal women. 1281 79

Release of tissue-type plasminogen activator (t-PA) from the vascular endothelium is paramount to endogenous thrombolysis potential. In addition to its vasodilator effects, nitric oxide (NO) has important antithrombotic properties, such as inhibition of platelet aggregation. It is currently not clear whether NO influences the capacity of the endothelium to release t-PA. The authors determined whether net endothelial t-PA release is regulated, at least in part, by NO. Endothelial t-PA release was determined, in vivo, in response to intrabrachial infusions of bradykinin (12.5-50.0 ng.100 mL tissue-1.min-1) in the presence and absence of the NO synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA; 5 mg/min) in 12 healthy men. Net release of t-PA across the forearm vascular bed was calculated as the product of arteriovenous concentration gradient and forearm plasma flow. The vasodilator response to bradykinin was significantly blunted ( approximately 30%) with l-NMMA. Although there was no effect of l-NMMA on basal t-PA release, acute release of t-PA to bradykinin was higher (P < 0.01) after (from -0.2 +/- 0.5 to 105.2 +/- 9.4 ng.100 mL tissue-1.min-1) versus before (from -0.4 +/- 0.7 to 48.7 +/- 7.3 ng.100 mL tissue-1.min-1) the administration of l-NMMA. Thus, in the absence of NO endothelial t-PA release was enhanced. These results suggest a potential regulatory influence of NO on bradykinin induced endothelial t-PA release.
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PMID:Endothelial release of tissue-type plasminogen activator in the human forearm: role of nitric oxide. 1288 37

The aim of the work was to study the influence of extracorporal circulation (ECC) on the vascular endothelial markers: von Willebrand factor (vWf), tissue plasminogen activator (t-PA) and trombomodulin (TM) in patients with coronary heart disease (CHD) undergoing coronary artery bypass graft (CABG). Examined group consisted of 30 patients (22 men, 8 women) at mean age 58.0 +/- 8.0 years, among them 19--were operated with ECC, 11--without ECC. Before and during operation blood was drawn 6 times. Control group consisted of 23. healthy volunteers at similar age. In the plasma vWf, t-PA and TM were determined with immunoenzymatic methods. Before operation the examined parameters were significantly higher compared to controls. The concentration of vWf during ECC was higher than in operation without ECC, but not significant. Differences statistically significant in the blood collected during ECC and without it appeared in t-PA only on the 3. and in TM on the 1. and 3. day after operation. It seems that ECC does not damage vascular endothelium direct, only indirect trough proinflammatory factors released from activated during ECC granulocytes and platelets.
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PMID:[Does extracorporeal circulation during coronary artery bypass grafting damage vascular endothelium?]. 1464 77

TRPV4 is a Ca(2+)- and Mg(2+)-permeable cation channel within the vanilloid receptor subgroup of the transient receptor potential (TRP) family, and it has been implicated in Ca(2+)-dependent signal transduction in several tissues, including brain and vascular endothelium. TRPV4-activating stimuli include osmotic cell swelling, heat, phorbol ester compounds, and 5',6'-epoxyeicosatrienoic acid, a cytochrome p450 epoxygenase metabolite of arachidonic acid (AA). It is presently unknown how these distinct activators converge on opening of the channel. Here, we demonstrate that blockers of phospholipase A(2) (PLA(2)) and cytochrome p450 epoxygenase inhibit activation of TRPV4 by osmotic cell swelling but not by heat and 4alpha-phorbol 12,13-didecanoate. Mutating a tyrosine residue (Tyr-555) in the N-terminal part of the third transmembrane domain to an alanine strongly impairs activation of TRPV4 by 4alpha-phorbol 12,13-didecanoate and heat but has no effect on activation by cell swelling or AA. We conclude that TRPV4-activating stimuli promote channel opening by means of distinct pathways. Cell swelling activates TRPV4 by means of the PLA(2)-dependent formation of AA, and its subsequent metabolization to 5',6'-epoxyeicosatrienoic acid by means of a cytochrome p450 epoxygenase-dependent pathway. Phorbol esters and heat operate by means of a distinct, PLA(2)- and cytochrome p450 epoxygenase-independent pathway, which critically depends on an aromatic residue at the N terminus of the third transmembrane domain.
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PMID:Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. 1469 Dec 63

Disturbances of lipids metabolism described in obese persons are important factor damaging vascular endothelium. Known markers of endothelium impairment are: von Willebrand factor (vWf), tissue plasminogen activator (t-PA:Ag) and thrombomodulin (TM). The aim of the work was to evaluate markers of the endothelial disturbance in the blood plasma of persons with obesity. The study was performed in the group of 50 obese persons (39 W, 11 M) aged 35-65 (means 48.8) years with abdominal obesity. The control group consisted of 30 healthy volunteers aged 25-56 (means 41.0) years. In the poor platelet plasma obtained from venous citric blood concentrations of TM, von Willebrand factor antigen (vWf:Ag) and tissue plasminogen activator antigen (t-PA:Ag) were determined using immunoenzyme-linked assay (ELISA). In the obese persons significantly higher concentration of vWf:Ag and t-PA:Ag in comparison to control group. Analysis of results obtained according sex showed that in the blood plasma of obese women TM concentration was significantly higher than in healthy women. Our study proved that in the blood plasma of obese men there are evidences of impairment of endothelial function as higher concentration of vWf:Ag and t-PA:Ag, but in the group of obese women as the increased TM concentration.
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PMID:[Thrombomodulin, von Willebrand factor and tissue plasminogen activator in the blood plasma of obese women and men]. 1505 51

We have shown that the capacity for local release of tissue-type plasminogen activator (tPA) from the vascular endothelium is impaired in patients with primary hypertension. Because this response is an important protective mechanism against intravascular clotting, we investigated whether this system is also defective in patients with advanced chronic kidney disease and hypertension. Nine nondiabetic nonsmoking men with chronic kidney disease (glomerular filtration rate 11 to 28 mL/min x 1.73 m2; aged 33 to 75 years) were compared with age-matched healthy controls. Intraarterial infusions of desmopressin, methacholine, and sodium nitroprusside were given locally in the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography and blood collected repeatedly during the desmopressin infusion for determination of stimulated net and total cumulated release of tPA. The maximal release rate of active tPA (P<0.05) and the capacity for acute tPA release were markedly impaired in the renal patients as compared with healthy subjects (ANOVA, P=0.013). Accordingly, the accumulated release of tPA was 1905 (SEM 366) and 3387 (718) ng/L tissue, respectively (P<0.05). However, there were no significant differences in vasodilator responses between the groups. Thus, patients with advanced chronic kidney disease and hypertension have a markedly impaired capacity for acute release of tissue plasminogen activator, despite preserved endothelium-dependent vasodilation. This defect may contribute to a defective local defense against arterial thrombosis.
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PMID:Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension. 1524 48

Endothelial release of tissue-type plasminogen activator (t-PA) regulates fibrinolysis and is considered to be a primary endogenous defense mechanism against thrombosis. Adiposity is associated with an increased risk of atherothrombotic events. We determined the influence of overweight and obesity on the capacity of the vascular endothelium to release t-PA and the effects of regular aerobic exercise on endothelial t-PA release in previously sedentary overweight and obese adults. First, we studied 66 sedentary adults: 28 normal-weight (BMI < 25 kg/m2); 22 overweight (BMI > or = 25 and < 30 kg/m2); and 16 obese (BMI > or = 30 kg/m2). Net endothelial t-PA release was determined in vivo in response to intrabrachial infusions of bradykinin (BK) and sodium nitroprusside. Second, we studied 17 overweight and obese adults who completed a 3-mo aerobic exercise intervention. Net release of t-PA in response to BK was approximately 45% lower (P < 0.01) in overweight (from 0.1 +/- 0.4 to 41.7 +/- 4.9 ng x 100 ml tissue(-1) x min(-1)) and obese (-0.1 +/- 0.6 to 47.7 +/- 5.2 ng x 100 ml tissue(-1) x min(-1)) compared with normal-weight (0.1 +/- 0.8 to 77.5 +/- 6.7 ng x 100 ml tissue(-1) x min(-1)) adults. There was no difference in t-PA release between the overweight and obese groups. Exercise training significantly increased t-PA release capacity in overweight and obese adults (from -0.3 +/- 0.5 to 37.1 +/- 4.9 ng x 100 ml tissue(-1) x min(-1) before training vs. 1.0 +/- 0.9 to 65.4 +/- 6.3 ng x 100 ml tissue(-1) x min(-1) after training) to levels comparable with those of their normal-weight peers. These results indicate that overweight and obesity are associated with profound endothelial fibrinolytic dysfunction. Importantly, however, regular aerobic exercise can increase the capacity of the endothelium to release t-PA in this at-risk population.
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PMID:Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise. 1598 56

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

Primary cultures of bovine microvascular endothelial cells (BME) isolated from the adrenal cortex, are commonly used to study vascular endothelium, but have a limited life span. To circumvent these limitations, we have immortalized BME cells with either simian virus 40 (SV40) or with a retrovirus containing the coding region of human telomerase reverse transcriptase (hTERT), and have investigated whether the clonal populations obtained, maintain differentiated properties characteristic of microvascular endothelium. Immortalized cells were characterized for maintenance of typical endothelial morphology, marker expression, and functional characteristics including uptake of Acetylated low-density lipoprotein (Ac-LDL), capillary-like tube formation in three-dimensional collagen gels, as well as metalloproteinase (MMP) and plasminogen activator (PA)-mediated extracellular proteolysis. Whilst immortalization of BME cells with SV40 was associated with loss of endothelial-specific properties, hTERT-BME exhibited an endothelial phenotype similar to that of wild-type endothelial cells. Specifically, they showed a typical cobblestone morphology, were contact-inhibited, expressed endothelial cell-specific markers (e.g., CD31, vWF) and both fibroblast growth factor receptor 1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, they expressed receptors for LDL. Importantly, when grown on collagen gels, hTERT-BME cells underwent MMP-dependent tube-like structure formation in response to VEGFR-2 activation. In a collagen gel sandwich assay, hTERT-BME formed tubular structures in the absence of exogenously added angiogenic cytokines. Sustained tube formation was induced by VEGF-A alone or in combination with FGF-2. From 17 sub-clones that displayed a non-transformed phenotype, a high proliferative capacity and tubulogenic properties in three-dimensional collagen gels, we isolated two distinct subpopulations that display a highly specific response to VEGF-A or to FGF-2. We have generated hTERT-BME cells that maintain endothelial-specific properties and function and have isolated clones that respond differentially to VEGF-A or FGF-2. These immortalized cell lines will facilitate the study of endothelial cell biology.
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PMID:Bovine microvascular endothelial cells immortalized with human telomerase. 1640 75


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