Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin activates platelets in an ordered sequence of events that includes shape change, increase in cytoplasmic Ca(2+), activation of the alphaIIbbeta3 integrin, granule secretion, aggregation, and formation of a stable hemostatic plug. Activation of this process has also been implicated in the pathogenesis of atherosclerosis, stroke, and thrombosis. There are two identified thrombin-activated receptors on the surface of human platelets. PAR1 is a high-affinity thrombin receptor, and PAR4 is a low apparent affinity thrombin receptor of uncertain function. The goal of these studies is to determine the kinetics of thrombin activation of PAR1 and PAR4 and to relate the individual inputs from each receptor to platelet Ca(2+) signaling, secondary autocrine stimulation, and aggregation. Using a combination of PAR-specific peptide ligands and anti-PAR1 reagents, we separated the biphasic thrombin Ca(2+) response of platelets into two discrete components-a rapid spike response caused by PAR1, followed by a slower prolonged response from PAR4. Despite having a 20-70-fold slower rate of activation, PAR4 produces the majority of the integrated Ca(2+) signal that is sustained by the continuous presence of catalytically active thrombin. Surprisingly, PAR4 activation is much more effective than PAR1 activation in mounting secondary autocrine Ca(2+) signals from secreted ADP. The strong ADP response due to activated PAR4, however, requires prior activation of PAR1 as would normally occur during treatment of platelets with thrombin. Thus, the late signal generated by activated PAR4 is not redundant with the early signal from PAR1 and instead serves to greatly extend the high intracellular Ca(2+) levels that support the late phase of the platelet aggregation process.
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PMID:Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. 1082 18

Thrombin, a plasma serine protease, plays a key role not only in coagulation and hemostasis but in thrombosis, restenosis and atherosclerosis. Thrombin activates platelets, endothelium, inflammatory cells and smooth muscle cells. The cellular action of thrombin is mediated by specific G-protein coupled thrombin receptors called proteinase-activated receptors (protease-activated receptor or PARs). Among the three thrombin receptors, PAR1 is the primary thrombin receptor in human and animal cells with an exception of non-primate platelets. An increased thrombin generation and PAR1 expression are observed on cells within atherosclerotic plaque and thrombus and following vascular injury. Animal studies with PAR1 deficient mice and small molecule antagonists indicate an important role of PAR1 in thrombosis and restenosis and thus the therapeutic potential of a PAR1 antagonist in treating these diseases. Development of a thrombin receptor tethered ligand analog binding assay led to the discovery of several different series of potent, nonpeptide small molecular antagonists of PAR1. These antagonists are PAR1 selective and inhibit most of the cellular effects of thrombin. A PAR1 antagonist has an advantage over a direct thrombin inhibitor since it does not inhibit enzymatic action of thrombin in the coagulation cascade with the consequent minimal bleeding side-effects, unlike a direct thrombin inhibitor. In addition, the emerging evidence for the role of PAR1 in various inflammatory diseases suggests as yet unexplored therapeutic potentials of PAR1 antagonists in various inflammatory diseases.
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PMID:Development of proteinase-activated receptor 1 antagonists as therapeutic agents for thrombosis, restenosis and inflammatory diseases. 1452 96

Autologous saphenous vein bypass grafts (SVG) are frequently compromised by neointimal thickening and subsequent atherosclerosis eventually leading to graft failure. Hyaluronic acid (HA) generated by smooth muscle cells (SMC) is thought to augment the progression of atherosclerosis. The aim of the present study was (1) to investigate HA accumulation in native and explanted arterialized SVG, (2) to identify factors that regulate HA synthase (HAS) expression and HA synthesis, and (3) to study the function of the HAS2 isoform. In native SVG, expression of all 3 HAS isoforms was detected by RT-PCR. Histochemistry revealed that native and arterialized human saphenous vein segments were characterized by marked deposition of HA in association with SMC. Interestingly, in contrast to native SVG, cyclooxygenase (COX)-2 expression by SMC and macrophages was detected only in arterialized SVG. In vitro in human venous SMC HAS isoforms were found to be differentially regulated. HAS2, HAS1, and HA synthesis were strongly induced by vasodilatory prostaglandins via Gs-coupled prostaglandin receptors. In addition, thrombin induced HAS2 via activation of PAR1 and interleukin 1beta was the only factor that induced HAS3. By small interfering RNA against HAS2, it was shown that HAS2 mediated HA synthesis is critically involved in cell cycle progression through G1/S phase and SMC proliferation. In conclusion, the present study shows that HA-rich extracellular matrix is maintained after arterialization of vein grafts and might contribute to graft failure because of its proproliferative function in venous SMC. Furthermore, COX-2-dependent prostaglandins may play a key role in the regulation of HA synthesis in arterialized vein grafts.
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PMID:Differential regulation of hyaluronic acid synthase isoforms in human saphenous vein smooth muscle cells: possible implications for vein graft stenosis. 1633 88

Monocytes are major mediators of inflammation, and apoptosis provides a mechanism for regulating the inflammatory response by eliminating activated macrophages. Furthermore, as a consequence of apoptosis, plasminogen binding is markedly increased on monocytoid cells. Therefore, we investigated the ability of plasminogen to modulate monocyte apoptosis. Apoptosis of monocytoid cells (human monocytes and U937 cells) was induced with either TNFalpha or cycloheximide. When apoptosis was induced in the presence of increasing concentrations of plasminogen, apoptosis was inhibited in a dose-dependent manner with full inhibition achieved at 2 microM plasminogen. Plasminogen treatment also markedly reduced internucleosomal DNA fragmentation and reduced levels of active caspase 3, caspase 8, and caspase 9 induced by TNFalpha or by cycloheximide. We examined the requirement for plasmin proteolytic activity in the cytoprotective function of plasminogen. A plasminogen active site mutant, [D(646)E]-Plg, failed to recapitulate the cytoprotective effect of wild-type plasminogen. Furthermore, antibodies against PAR1 blocked the antiapoptotic effect of plasminogen. Our results suggest that plasminogen inhibits monocyte apoptosis. The cytoprotective effect of plasminogen requires plasmin proteolytic activity and requires PAR1. Because apoptosis of monocytes plays a key role in inflammation and atherosclerosis, these results provide insight into a novel role of plasminogen in these processes.
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PMID:Plasminogen inhibits TNFalpha-induced apoptosis in monocytes. 1647 87

In this study we examined the ability of tissue factor (TF) alone, or in conjunction with factor VIIa, factor Xa and TFPI in activating a number of key signalling pathways associated with cellular growth, stress and differentiation responses in human endothelial cells. We used luciferase reporter systems to demonstrate the activation of p42/44 MAPK by the TF-FVIIa complex, mediated via the PAR1 receptor. TF alone was capable of interacting with the cell surface and was sufficient to activate the JNK-SAPK pathway and subsequently AP-1, but the level of activation was enhanced by the activity of FXa on PAR1 and 2. Furthermore, the phosphorylated form of the transmembrane-cytoplasmic domain of TF was directly responsible for activation of these pathways. CREB activation occurred in response to TF-FVIIa in a non-protease dependent manner but was lowered on addition of FXa. Finally, NFkappaB activation occurred in response to FVIIa or FXa, with the latter exhibiting higher levels of activation. In conclusion, we have shown that TF is capable of activating differing signalling pathways, via more than one mechanism. The differential influence of TF is modified depending on the presence of other coagulation factors and ultimately acts as a deciding factor in the determination of cellular fate.
Atherosclerosis 2007 Sep
PMID:Differential functions of tissue factor in the trans-activation of cellular signalling pathways. 1713 81

Factor VIIa (FVIIa)-induced signal transduction is strongly dependent on cellular surface expression of Tissue Factor (TF) and Protease Activated Receptors (PARs). FVIIa signals primarily through PAR2. This contrasts to thrombin which signals primarily via PAR1 and does so without the assistance of a co-receptor, but by binding to an exosite on PAR1. Various TF:FVII-mediated cellular activities are now well documented and have indicated possible links to inflammation, atherosclerosis, angiogenesis, tissue repair, tumor growth and metastasis. Further knowledge about cellular responses induced by coagulation factors has been obtained by gene-expression profiling of MDA-MB-231 cells stimulated with FVIIa or alternatively with PAR1 or PAR2 agonist peptides. These studies and qPCR measurements of the transcription of selected genes in these and other carcinoma cell lines have provided new information about gene expression induced by PAR activation, the gene repertoire induced by TF:FVIIa via PAR2, and how it differs from that induced via PAR1 by thrombin.
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PMID:Microarray studies of factor VIIa-activated cancer cells. 1869 91

Human cytomegalovirus (HCMV) establishes a life-long persistent infection. HCMV infection could be associated with chronic inflammatory diseases, such as cardiovascular disease and atherosclerosis. Here we observed that in HCMV (AD-169) pre-exposed human umbilical vein endothelial cells (HUVEC), thrombin-induced expression of IL-1alpha and M-CSF is markedly enhanced compared to the un-exposed cells. Study of the expression of thrombin receptor genes in HUVEC showed that HCMV triggered a time- and concentration-dependent expression of the thrombin receptors PAR1, PAR3 and PAR4 at the mRNA level. Induction of PAR1 and PAR3 mRNA expression is due to transcriptional activation of their promoters as shown by gene reporter assay. Furthermore, the virus induced expression of PAR1 and PAR3 but not PAR4 proteins, as analyzed by Western immunoblotting. However, flow cytometric analysis revealed that only PAR3, expressed at very low level in control HUVEC, is induced at the surface during the exposure to the virus. Our data suggest that although exposure to HCMV induces a minor increase of cell-surface receptors expression, it does make endothelial cells more responsive to additional thrombin stimulation.
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PMID:Human cytomegalovirus increases HUVEC sensitivity to thrombin and modulates expression of thrombin receptors. 2015 36

Protease activated receptors (PARs) are a small family of G protein-coupled receptors (GPCR) mediating the cellular effects of some proteases of the coagulation system, such as thrombin, or other proteases, such as trypsin or metalloproteinase 1. As the prototype of PARs, PAR1 is a seven transmembrane GPCR that, upon cleavage by thrombin, unmasks a new amino-terminus able to bind intramolecularly to PAR1 itself thus inducing signaling. In the vascular system, thrombin and other proteases of the coagulation-fibrinolysis system, such as plasmin, factor VIIa and factor Xa, activated protein C, are considered physiologically relevant agonists, and PARs appear to largely account for the cellular effects of these enzymes. In the vasculature, PARs are expressed on platelets, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In the vessel wall, under physiological conditions, PARs are mainly expressed in ECs and participate in the regulation of vascular tone, by inducing endothelium-dependent relaxation. PAR activation on ECs promotes conversion of these cells into a proinflammatory phenotype, causes increase of vascular permeability, and the exposure/secretion of proteins and cytokines mediating the local accumulation of platelets and leukocytes. These effects contribute to the vascular consequences of sepsis and of diseases such as acute lung injury and acute respiratory distress syndrome. In normal arteries PARs are to a much lesser amount expressed on VSMCs. However, in conditions associated with endothelial dysfunction, PARs mediate contraction, proliferation, migration, hypertrophy of VSMCs and their production of extracellular matrix, thereby contributing to the pathophysiology of atherosclerosis and hypertension. Inhibition of protease-PAR interaction might thus become a potential therapeutic target in various vascular diseases.
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PMID:Functional role of protease activated receptors in vascular biology. 2492 9

Activated platelets and neutrophils exacerbate atherosclerosis. Platelets release the chemokines CXCL4, CXCL4L1 and CCL5, whereas myeloperoxidase (MPO) and azurocidin are neutrophil-derived. We investigated whether plasma levels of these platelet and neutrophil mediators are affected by the acute coronary syndrome (ACS), its medical treatment, concomitant clinical or laboratory parameters, and predictive for the progression of coronary artery disease (CAD). In an observational study, the association of various factors with plasma concentrations of platelet chemokines and neutrophil mediators in 204 patients, either upon admission with ACS and 6 hours later or without ACS or CAD, was determined by multiple linear regression. Mediator release was further analysed after activation of blood with ACS-associated triggers such as plaque material. CXCL4, CXCL4L1, CCL5, MPO and azurocidin levels were elevated in ACS. CXCL4 and CCL5 but not CXCL4L1 or MPO were associated with platelet counts and CRP. CXCL4 (in association with heparin treatment) and MPO declined over 6 hours during ACS. Elevated CCL5 was associated with a progression of CAD. Incubating blood with plaque material, PAR1 and PAR4 activation induced a marked release of CXCL4 and CCL5, whereas CXCL4L1 and MPO were hardly or not altered. Platelet chemokines and neutrophil products are concomitantly elevated in ACS and differentially modulated by heparin treatment. CCL5 levels during ACS predict a progression of preexisting CAD. Platelet-derived products appear to dominate the inflammatory response during ACS, adding to the emerging evidence that ACS per se may promote vascular inflammation.
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PMID:Inflammatory role and prognostic value of platelet chemokines in acute coronary syndrome. 2539 54

From the discovery of protease activated receptors (PARs) to the development of first clinically available PAR1 antagonist (vorapaxar) more than two decades of continuous research have passed. There are four different types of PARs named as PAR1, 2, 3 and 4 having a unique mechanism of signaling. These receptors are present in different organs, including the cardiovascular system. Presence of PARs in heart and blood vessels, alteration in the level and activity of the receptors in pathological conditions along with availability of antagonists makes these receptors targetable in several cardiac diseases. Therapeutic benefits of PAR antagonist have been proven in animal model of cardiac diseases such as myocardial infarction, viral myocarditis, atherosclerosis, pulmonary arterial hypertension, etc. PAR signaling plays a vital role in mediating cardiac hypertrophy, inflammation and fibrosis. Apart from having cardiac importance PAR antagonist are also continuously experimented for their beneficial effects in improving insulin resistance in metabolic syndromes. In the present review, we have discussed the functions of individual PARs in the heart and blood vessels along with the expected usefulness of PAR modulators in cardiovascular diseases.
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PMID:Therapeutic Potential of Targeting Protease Activated Receptors in Cardiovascular Diseases. 2647 18


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