The roles and mechanisms of PAR4 and P2Y<sub>12</sub>/phosphatidylinositol 3‐kinase pathway in maintaining thrombin‐induced platelet aggregation

Wu, Chin Chung; Wu, Shih Yun; Liao, Chieh Yu; Teng, Che-Ming; Wu, Yang; Kuo, Sheng Chu

doi:10.1111/j.1476-5381.2010.00921.x

Cited by 50 publications

(43 citation statements)

References 52 publications

(69 reference statements)

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“…34 A certain focus in this line of research had been on candidate genes involved in malignant disease, rendering the findings of 2 recent epigenome-wide studies with single base resolution 35,36 all the more interesting: of some 27 000 cytosine neighbored by guanine sites covered by the assay used, the one with the statistically most significant association with smoking behavior was located in F2RL3, a gene coding for proteinase-activated receptor 4. Proteinase-activated receptor 4 has been implicated in cardiovascular pathophysiology, especially inflammation, 37 platelet function, 38 and possibly perioperative myocardial injury after bypass surgery. 39 Subsequently, a pronounced association of lower F2RL3 methylation with higher mortality (both cardiovascular and noncardiovascular) was demonstrated in a cohort of patients with stable coronary heart disease.…”

Section: Epigenetics Of Tobacco-associated Cardiovascular Diseasementioning

confidence: 99%

“…Proteinase-activated receptor 4 has been implicated in cardiovascular pathophysiology, especially inflammation, 37 platelet function, 38 and possibly perioperative myocardial injury after bypass surgery. 39 Subsequently, a pronounced association of lower F2RL3 methylation with higher mortality (both cardiovascular and noncardiovascular) was demonstrated in a cohort of patients with stable coronary heart disease.…”

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confidence: 99%

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Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Breitling¹

2013

ATVB

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Abstract-Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Tobacco-smoking, one of the most important cardiovascular risk factors, is itself partially determined by genetic background and is associated with altered epigenetic patterns. This could render the genetics and epigenetics of smoking-related cardiovascular disease a textbook example of environmental epigenetics and modern approaches to multimodal data analysis. A pronounced association of smoking-related methylation patterns in the F2RL3 gene with prognosis in patients with stable coronary heart disease has recently been described. Nonetheless, surprisingly little concrete knowledge on the role of specific genetic variants and epigenetic modifications in the development of cardiovascular diseases in people who smoke has been accumulated. Beyond the current knowledge, the present review briefly outlines some chief challenges and priorities for moving forward in this field. variation in antioxidative resilience seems to have no clinical cardiovascular consequences by itself, but-in interaction with the excessive oxidative stress caused by smoking-it means that smoking-associated cardiovascular risks are much greater in ε4 carriers than in other subjects. 10 It has been realized that such gene-environment interactions could also interfere with the performance of lipid-lowering drugs, but the extent of this potentially far-reaching problem still needs to be clarified. 11Given the multitude of physiological phenomena involved in tobacco-smoking-related cardiovascular disease (ref. 12 for an informative overview), it is hardly surprising that similar interactions with smoking have been reported for sequence variants in candidate genes coding for proteins as diverse as lipoprotein lipase and interleukin-6, 10 prothrombotic mutations like factor II G20210A, 13 or transforming growth factor-β1.14 One study investigating an interaction of interleukin-18 polymorphisms with smoking regarding cardiovascular disease risk was exceptional for its laudable collaborative design emphasizing statistical power.15 Nonetheless, the level of evidence for the vast majority of currently suggested gene-smoking interactions ultimately remains very limited. The evolution of findings concerning an interaction between tobacco-smoking and variants in glutathione S-transferase genes with respect to cardiovascular disease risk-which started out as a seemingly plausible effect modification supported by multiple lines of evidence 8 and was further sugested later meta-analysis, 16 only to vanish with subsequent sample size escalation 17 -should be taken as a reminder of the danger of prematurely overinterpreting gene-smoking interactions or even higher order interactions (eg, gene-age-smoking). 18Thorough replication and follow-up studies need to become more of a norm in this statistically challenging field. A New Era of EpigeneticsStudies on epigenetic aspects of health and disease have exploded in recent years, mainly because of technological a...

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Section: Epigenetics Of Tobacco-associated Cardiovascular Diseasementioning

confidence: 99%

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confidence: 99%

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Breitling¹

2013

ATVB

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“…Human platelets express two functional thrombin receptors, PAR1 and PAR4 (63)(64)(65). Thrombin acts through PAR1 and PAR4 on human platelets to signal activation responses, such as calcium mobilization, release of procoagulant molecules (e.g., P-selectin) from α-granules, release of small molecules (e.g., ADP) from dense granules, activation of glycoprotein IIbIIIa/integrin α IIb β 3 (GPIIbIIIa) and aggregation (65)(66)(67)(68)(69)(70)(71)(72). Thrombin activates PAR1 at concentrations 10-fold less than PAR4, but activation of PAR4 provides a longer stimulus (61,73).…”

Section: Action Of Par-mediated Thrombin On Plateletsmentioning

confidence: 99%

Protease-activated receptors in cancer: A systematic review

Han

Jin

et al. 2011

Oncology Letters

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Abstract. The traditional view of the role of proteases in tumor growth, progression and metastasis has significantly changed. Apart from their contribution to cancer progression, it is evident that a subclass of proteases, such as thrombin, serves as signal molecules controlling cell functions through the protease-activated receptors (PARs). Among the four types of PAR (PAR1-4; cloned and named in order of their discovery), PAR1, PAR3 and PAR4 are activated by thrombin, unlike PAR2, which is activated by trypsin-like serine proteases. Thrombin has been proven to be a significant factor in both the behavior of cancer in its involvement in hemostasis and blood coagulation. Thrombin is a key supporter of various cellular effects relevant to tumor growth and metastasis, as well as a potent activator of angiogenesis, which is essential for the growth and development of all solid tumor types. This review presents an overview of the role of PAR-mediated thrombin in angiogenesis and cancer, focusing on the ability of PAR1-and PAR4-mediated thrombin to affect tumorigenesis and angiogenesis.

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“…Excess ADP has been shown to regulate the P2Y12/phosphatidylinositol-3 kinase (PI3K) pathway that is essential for stable platelet aggregation. 5 Furthermore, the release of ADP enhances platelet aggregation by increasing lectin-like oxidized lowdensity lipoprotein (LDL) receptor-1 (LOX-1) expression and by mediating the inside-out integrin signaling-dependent activation of glycoprotein (GP)IIb/IIIa. 6 Therefore, the use of pharmacologic therapies such as aspirin, 7 clopidogrel, 8 and GPIIb/IIIa inhibitors 9 to inhibit platelet activation is paramount for preventing the onset and recurrence of acute coronary syndrome.…”

Section: Introductionmentioning

confidence: 99%

Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation

Chan

Chu

et al. 2013

Blood

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Key Points• Highly electronegative LDL (L5), which is elevated in patients with STEMI, induces platelet activation and aggregation through LOX-1.• L5 may have a role in promoting thrombogenesis that leads to STEMI.Platelet activation and aggregation underlie acute thrombosis that leads to ST-elevation myocardial infarction (STEMI). L5-highly electronegative low-density lipoprotein (LDL)-is significantly elevated in patients with STEMI. Thus, we examined the role of L5 in thrombogenesis. Plasma LDL from patients with STEMI (n 5 30) was chromatographically resolved into 5 subfractions (L1-L5) with increasing electronegativity. In vitro, L5 enhanced adenosine diphosphate-stimulated platelet aggregation twofold more than did L1 and induced platelet-endothelial cell (EC) adhesion. L5 also increased P-selectin expression and glycoprotein (GP)IIb/IIIa activation and decreased cyclic adenosine monophosphate levels (n 5 6, P < .01) in platelets. In vivo, injection of L5 (5 mg/kg) into C57BL/6 mice twice weekly for 6 weeks shortened tail bleeding time by 43% (n 5 3; P < .01 vs L1-injected mice) and increased P-selectin expression and GPIIb/IIIa activation in platelets. Pharmacologic blockade experiments revealed that L5 signals through plateletactivating factor receptor and lectin-like oxidized LDL receptor-1 to attenuate Akt activation and trigger granule release and GPIIb/IIIa activation via protein kinase C-a. L5 but not L1 induced tissue factor and P-selectin expression in human aortic ECs (P < .01), thereby triggering platelet activation and aggregation with activated ECs. These findings indicate that elevated plasma levels of L5 may promote thrombosis that leads to STEMI. (Blood. 2013;122(22):3632-3641)

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The roles and mechanisms of PAR4 and P2Y₁₂/phosphatidylinositol 3‐kinase pathway in maintaining thrombin‐induced platelet aggregation

Abstract: These results suggest that PAR4 acts in parallel with the P2Y(12)/PI3K pathway to stabilize platelet aggregates, and provide new insights into the mechanisms of thrombus stabilization and potential applications for antithrombotic therapy.

Cited by 50 publications

References 52 publications

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Protease-activated receptors in cancer: A systematic review

Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation

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The roles and mechanisms of PAR4 and P2Y12/phosphatidylinositol 3‐kinase pathway in maintaining thrombin‐induced platelet aggregation

Abstract: These results suggest that PAR4 acts in parallel with the P2Y(12)/PI3K pathway to stabilize platelet aggregates, and provide new insights into the mechanisms of thrombus stabilization and potential applications for antithrombotic therapy.

Cited by 50 publications

References 52 publications

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Protease-activated receptors in cancer: A systematic review

Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation

Contact Info

Product

Resources

About

The roles and mechanisms of PAR4 and P2Y₁₂/phosphatidylinositol 3‐kinase pathway in maintaining thrombin‐induced platelet aggregation