Species differences in platelet responses to thrombin and SFLLRN. Receptor-mediated calcium mobilization and aggregation, and regulation by protein kinases

Derian, Claudia K.; Santulli, Rosemary; Tomko, Karen A.; Haertlein, Barbara J.; Andrade‐Gordon, Patricia

doi:10.1016/0049-3848(95)00084-5

Cited by 70 publications

(50 citation statements)

References 24 publications

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“…For example, although PAR-1 mediates thrombin-induced platelet aggregation in humans, 14 PAR-1 is not expressed in mouse, rat, and rabbit platelets and thus, does not mediate thrombin-induced platelet aggregation in these species. 32,33 The response to thrombin in mouse and rat platelets appears to be mediated by PAR-3 and PAR-4, 42,43 2 distinct protease-activated thrombin receptors. Because platelet adhesion, aggregation, and degranulation are important components of the vascular injury process, 44,45 these plateletdependent processes would not be affected in PAR-1-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Altered Vascular Injury Responses in Mice Deficient in Protease-Activated Receptor-1

Cheung

D’Andrea

Andrade‐Gordon

et al. 1999

ATVB

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115

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Abstract-Expression of protease-activated receptor-1 (PAR-1), a cell-surface receptor for thrombin, is increased in balloon-injured rat carotid artery and human atherosclerotic tissue. To examine the role of PAR-1 in vascular injury, we compared vascular injury responses in wild-type (WT) and PAR-1-deficient (PAR-1 Ϫ/Ϫ ) mice. Arterial injury was induced by inserting a flexible guidewire into the common carotid artery and withdrawing it 6 times with rotation. Bromodeoxyuridine, delivered subcutaneously by osmotic minipump, was used to measure cellular proliferation. Mice were perfusion-fixed at 1, 2, 5, 10, and 14 days after injury. Extensive endothelial damage, mural thrombosis, platelet adherence, and medial smooth muscle cell loss and necrosis were apparent at day 1 in both WT and PAR-1 Ϫ/Ϫ mice. The incidence of thrombosis or platelet deposition in WT and PAR-1 Ϫ/Ϫ mice declined from 100% at day 1 to 25% and 21%, respectively, at 14 days. Endothelial disruption, as assessed by Evan's blue uptake, was maximum at day 1 and declined by day 14. This apparent endothelial regrowth was similar in WT and PAR-1 Ϫ/Ϫ mice. Significant medial thickening at 14 days after injury was similar in WT (from 22.8Ϯ1.7 to 30.7Ϯ1.9 m) and PAR-1 Ϫ/Ϫ (from 23.2Ϯ2.1 to 30.5Ϯ2.2 m) mice. Medial area also increased in response to injury but to a lesser extent in PAR-1 Ϫ/Ϫ mice (from 0.0250Ϯ0.0044 to 0.0312Ϯ0.0047 mm 2 ) than in WT mice (from 0.0266Ϯ0.0040 to 0.0398Ϯ0.0050 mm 2 ). Neointima was variable and occurred in 6 of 13 WT and 5 of 12 PAR-1 Ϫ/Ϫ mice. However, intimal area tended to be less in PAR-1 Ϫ/Ϫ mice (0.0016Ϯ0.0007 mm 2 ) compared with WT mice (0.0082Ϯ0.0032 mm 2 ), although this difference did not achieve statistical significance (Pϭ0.06). Cell density was significantly greater in normal carotids from PAR-1 Ϫ/Ϫ (6.4Ϯ0.5ϫ10 3 /mm 2 ) compared with WT (4.3Ϯ0.8ϫ10 3 /mm 2 ) mice and remained elevated after injury. Vessel and lumen diameters tended to increase in WT mice after injury, whereas vessel diameter was unchanged and lumen diameter actually decreased in PAR-1 Ϫ/Ϫ mice. Cell proliferation in injured carotid arteries was similar in PAR-1 Ϫ/Ϫ and WT mice. Key Words: protease-activated receptor Ⅲ knockout mouse Ⅲ thrombin Ⅲ thrombin receptor Ⅲ cell proliferation S everal lines of evidence suggest a significant role for thrombin in vascular injury responses associated with thrombosis, atherosclerosis, and mechanical arterial injury, such as that caused by balloon angioplasty or stent implantation. [1][2][3] Concentrations of thrombin at sites of vascular injury are significantly elevated. For example, 5 hours after balloon injury of the rabbit aorta, thrombin activity was 50 fmol ⅐ min Ϫ1 ⅐ cm Ϫ2 , gradually decreasing to 10 fmol ⅐ min Ϫ1 ⅐ cm Ϫ2 at 24 hours after injury. 4 These levels were sustained for at least 10 days. In human plasma, thrombin concentrations in the vicinity of a thrombus have been estimated to be as high as 140 nmol/L. 5 In addition to evidence for elevated thrombin levels at sites of vascular injury...

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Section: Discussionmentioning

confidence: 99%

Altered Vascular Injury Responses in Mice Deficient in Protease-Activated Receptor-1

Cheung

D’Andrea

Andrade‐Gordon

et al. 1999

ATVB

Self Cite

115

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“…PAR1-activating peptides did not activate rodent platelets (12)(13)(14), and platelets from PAR1-deficient mice responded like wild-type platelets to thrombin (14). This observation prompted a search for additional thrombin receptors and led to the identification of PAR3 (15).…”

Section: Introductionmentioning

confidence: 99%

Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin

Kahn

Nakanishi‐Matsui²,

Shapiro³

et al. 1999

J. Clin. Invest.

756

628

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“…To examine the role of PAR-1 in arterial thrombosis, as well as to elucidate a potential role for PAR-4, we have developed selective PAR-1 antagonists, exemplified by RWJ-58259 (Andrade-Gordon et al, 2001;Zhang et al, 2001). Unfortunately, the evaluation of RWJ-58259 in smallanimal models of thrombosis has been hindered by the species-dependent expression of PAR-1 in platelets (Connolly et al, 1994(Connolly et al, , 1996Derian et al, 1995;Darrow et al, 1996). Because guinea pigs were identified as the only small animal possessing PAR-1 on their platelets, we studied the effect of PAR-1 inhibition with RWJ-58259 in two guinea pig models of arterial thrombosis ).…”

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confidence: 99%

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Derian¹,

Damiano²,

Addo³

et al. 2003

J Pharmacol Exp Ther

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154

127

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Although it is well recognized that human platelet responses to ␣-thrombin are mediated by the protease-activated receptors PAR-1 and PAR-4, their role and relative importance in plateletdependent human disease has not yet been elucidated. Because the expression profile of PARs in platelets from nonprimates differs from humans, we used cynomolgus monkeys to evaluate the role of PAR-1 in thrombosis. Based on reverse transcription-polymerase chain reaction, PAR expression in platelets from cynomolgus monkeys consisted primarily of PAR-1 and PAR-4, thereby mirroring the profile of human platelets. We probed the role of PAR-1 in a primate model of vascular injury-induced thrombosis with the selective PAR-1 antagonist (␣S)

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Species differences in platelet responses to thrombin and SFLLRN. Receptor-mediated calcium mobilization and aggregation, and regulation by protein kinases

Cited by 70 publications

References 24 publications

Altered Vascular Injury Responses in Mice Deficient in Protease-Activated Receptor-1

Altered Vascular Injury Responses in Mice Deficient in Protease-Activated Receptor-1

Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

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