Is thrombin a key player in the 'coagulation-atherogenesis' maze?

Borissoff, Julian Ilcheff; Spronk, Henri M. H.; Heeneman, Sylvia; Cate, Hugo Ten

doi:10.1093/cvr/cvp066

Cited by 201 publications

(179 citation statements)

References 130 publications

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“…One possible mechanism that might explain the abundant presence and functional activity of coagulation proteins in the early stage of atherosclerosis is that many of the coagulation proteins help to propagate the atheromatous plaque by inducing multiple proatherogenic actions such as cellular adhesion, migration, angiogenesis, and inflammation. 7,12 In addition to their prothrombotic nature, coagulation proteases induce cell proliferation, 6 and the latter are of great importance in determining the stability of an atherosclerotic lesion. The abundance of almost all (intrinsic and extrinsic) coagulation proteins suggests that the generation of thrombin is an active process during atherogenesis, supporting a major role of thrombin (and possibly fibrin) in this condition.…”

Section: Discussionmentioning

confidence: 99%

“…12 Direct evidence for the role of thrombin in the atherogenic process comes from experiments showing reduced progression of atherosclerosis in apolipoprotein E Ϫ/Ϫ mice on pharmacological inhibition of thrombin. 13 Moreover, decreased expression of TF pathway inhibitor (TFPI) on an apolipoprotein E Ϫ/Ϫ background increased the atherosclerotic burden.…”

Section: Clinical Perspective On P 830mentioning

confidence: 99%

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Early Atherosclerosis Exhibits an Enhanced Procoagulant State

et al. 2010

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Background-Thrombin generation in vivo may be important in regulating atherosclerotic progression. In the present study, we examined for the first time the activity and presence of relevant coagulation proteins in relation to the progression of atherosclerosis. Methods and Results-Both early and stable advanced atherosclerotic lesions were collected pairwise from each individual (nϭ27) during autopsy. Tissue homogenates were prepared from both total plaques and isolated plaque layers, in which the activity of factors (F) II, X, and XII and tissue factor was determined. Microarray analysis was implemented to elucidate local messenger RNA synthesis of coagulation proteins. Part of each specimen was paraffin embedded, and histological sections were immunohistochemically stained for multiple coagulation markers with the use of commercial antibodies. Data are expressed as median (interquartile range [IQR] Key Words: atherosclerosis Ⅲ hypercoagulability Ⅲ immunohistochemistry Ⅲ plaque Ⅲ thrombosis A therosclerosis is widely recognized as a chronic inflammatory disease. 1 Rupture of an atherosclerotic plaque is considered the predominant underlying cause of acute atherothrombotic events such as myocardial infarction, ischemic stroke, and vascular death. A close relation between blood coagulation and atherosclerosis 2,3 is supported by studies revealing the presence of specific coagulation proteins within an atherosclerotic lesion. Tissue factor (TF) and factor (F) VII, of which the complex is the principal initiator of coagulation in vivo, are expressed on macrophages and vascular smooth muscle cells (SMC) within the arterial vessel wall and atherosclerotic lesion. 4,5 Both proteins potentially participate in multiple proatherogenic processes such as migration and proliferation of SMC, 6 inflammation, and angiogenesis. 7 In addition to the single effects of each protein, the local interaction between macrophage/SMC-derived TF and FVII may provide a catalytic complex for subsequent generation of thrombin and fibrin, of which the latter is also detectable in atherosclerotic lesions. 8,9 The procoagulant condition of the atherosclerotic lesion may be further enhanced by the presence of various proinflammatory cytokines (eg, tumor necrosis factor-␣, interleukin-1 10 ), which may downregulate local expression of anticoagulant proteins such as thrombomodulin and the endothelial protein C receptor on endothelial cells. 11 Received September 4, 2009; accepted June 28, 2010 Clinical Perspective on p 830Thrombin, a key enzyme in blood coagulation, may also play a critical role in many processes related to the development, progression, and atherothrombotic potential of atherosclerotic plaques. 12 Direct evidence for the role of thrombin in the atherogenic process comes from experiments showing reduced progression of atherosclerosis in apolipoprotein E Ϫ/Ϫ mice on pharmacological inhibition of thrombin. 13 Moreover, decreased expression of TF pathway inhibitor (TFPI) on an apolipoprotein E Ϫ/Ϫ background increased the atheroscle...

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Perspective On P 830mentioning

confidence: 99%

Early Atherosclerosis Exhibits an Enhanced Procoagulant State

et al. 2010

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“…Much evidence suggests that thrombin acts as a powerful modulator in the progression of atherosclerosis [43] . Overexpression of CTGF has been found in atherosclerotic carotid arteries and in the aortic wall from patient with thoracic aortic dissection [8,44] .…”

Section: Discussionmentioning

confidence: 99%

Thrombin induced connective tissue growth factor expression in rat vascular smooth muscle cells via the PAR-1/JNK/AP-1 pathway

Chen²,

Hsu³

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the signaling pathways involved in thrombin-induced connective tissue growth factor (CTGF) expression in rat vascular smooth muscle cells (VSMCs). Methods: Experiments were preformed on primary rat aortic smooth muscle cells (RASMCs) and a rat VSMC line (A10). CTGF protein levels were measured using Western blotting. Luciferase reporter genes and dominant negative mutants (DNs) were used to investigate the signaling pathways mediating the induction of CTGF expression by thrombin. Results: Thrombin (0.3-3.0 U/mL) caused a concentration-and time-dependent increase in CTGF expression in both RASMCs and A10 cells. Pretreating A10 cells with the protease-activated receptor 1 (PAR-1) antagonist SCH79797 (0.1 µmol/L) significantly blocked thrombin-induced CTGF expression, while the PAR-4 antagonist tcY-NH 2 (30 µmol/L) had no effect. The PAR-1 agonist SFLLRN-NH 2 (300 µmol/L) induced CTGF expression, while the PAR-4 agonist GYPGQV-NH 2 (300 µmol/L) had no effect. Thrombin (1 U/mL) caused time-dependent phosphorylation of c-Jun N-terminal kinase (JNK). Pretreating with the JNK inhibitor SP600125 (3-30 µmol/L) or transfection with DNs of JNK1/2 significantly attenuated thrombin-induced CTGF expression. Thrombin (0.3-3.0 U/mL) increased activator protein-1 (AP-1)-luciferase activity, which was inhibited by the JNK inhibitor SP600125. The AP-1 inhibitor curcumin (1-10 µmol/L) concentration-dependently attenuated thrombin-induced CTGF expression. Conclusion: Thrombin acts on PAR-1 to activate the JNK signaling pathway, which in turn initiates AP-1 activation and ultimately induces CTGF expression in VSMCs.

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“…There was no analog reaction as far as MCP was concerned [20]. Increased DAF expression found in our studies can be explained as a secondary response of placental tissue to inflammatory reaction and the presence of proinflammatory cytokine that can activate complement cascade in a secondary way [9,10,20]. Lack of similar observations in MCP in the referenced literature might be a result of the limited possibilities of an in vitro model.…”

Section: Discussionmentioning

confidence: 67%

Complement inhibitory proteins expression in placentas of thrombophilic women

Wirstlein¹,

Jasiński²,

Rajewski³

et al. 2012

Folia Histochem Cytobiol.

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Abstract:Factors controlling complement activation appear to exert a protective effect on pregnancy. This is particularly important in women with thrombophilia. The aim of this study was to determine the transcript and protein levels of complement decay-accelerating factor (DAF) and membrane cofactor protein (MCP) in the placentas of women with acquired and inherited thrombophilia. Also, we assessed immunohistochemistry staining of inhibitors of the complement cascade, DAF and MCP proteins, in the placentas of thrombophilic women. Placentas were collected from eight women with inherited thrombophilia and ten with acquired thrombophilia. The levels of DAF and MCP transcripts were evaluated by qPCR, the protein level was evaluated by Western blot. We observed a higher transcript (p < 0.05) and protein (p < 0.001) levels of DAF and MCP in the placentas of thrombophilic women than in the control group. DAF and MCP were localized on villous syncytiotrophoblast membranes, but the assessment of staining in all groups did not differ. The observed higher expression level of proteins that control activation of complement control proteins is only seemingly contradictory to the changes observed for example in the antiphospholipid syndrome. However, given the hitherto known biochemical changes associated with thrombophilia, a mechanism in which increased expression of DAF and MCP in the placentas is an effect of proinflammatory cytokines, which accompanies thrombophilia, is probable.

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Is thrombin a key player in the 'coagulation-atherogenesis' maze?

Cited by 201 publications

References 130 publications

Early Atherosclerosis Exhibits an Enhanced Procoagulant State

Early Atherosclerosis Exhibits an Enhanced Procoagulant State

Thrombin induced connective tissue growth factor expression in rat vascular smooth muscle cells via the PAR-1/JNK/AP-1 pathway

Complement inhibitory proteins expression in placentas of thrombophilic women

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