Protease-Activated Receptors in Cardiovascular Diseases

Leger, Andrew J.; Covic, Lidija; Kuliopulos, Athan

doi:10.1161/circulationaha.105.574830

Cited by 260 publications

(268 citation statements)

References 78 publications

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“…PARs play crucial roles in coagulation and vascular homeostasis [29] . Overexpression of PAR-1 has been found in the VSMCs from thickening intimas of human atherosclerotic arteries [30] .…”

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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“…PARs play crucial roles in coagulation and vascular homeostasis [29] . Overexpression of PAR-1 has been found in the VSMCs from thickening intimas of human atherosclerotic arteries [30] .…”

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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“…18 Matrix metalloproteinase-1 is known to activate PAR-1, 33 which plays critical roles in coagulation, inflammation, and vascular homeostasis 34 ; and its expression is increased in preeclamptic compared with healthy placentas. 35 We hypothesized that neutrophils infiltrated into the vasculature of women with preeclampsia promote VSMC expression of PAR-1.…”

Section: Vascular Par-1 Is Increased In Preeclampsiamentioning

confidence: 99%

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

Estrada-Gutiérrez

Cappello

Mishra

et al. 2011

The American Journal of Pathology

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This study was conducted to determine the following: (1) whether matrix metalloproteinase-1 (MMP-1) is increased in systemic vessels of preeclamptic women, (2) whether this increase might be mediated by neutrophils, and (3) whether MMP-1 could be responsible for vascular dysfunction. Omental arteries and plasma were collected from healthy pregnant and preeclamptic women. Omental arteries were evaluated for gene and protein expression of MMP-1, collagen type 1␣, tissue inhibitor of metalloproteinase-1, and vascular reactivity to MMP-1. Gene and protein expression levels were also evaluated in human vascular smooth muscle cells (VSMCs) co-cultured with activated neutrophils, reactive oxygen species, or tumor necrosis factor ␣. Vessel expression of MMP-1 and circulating MMP-1 levels were increased in preeclamptic women, whereas vascular expression of collagen or tissue inhibitor of metalloproteinase-1 were down-regulated or unchanged. In cultured VSMCs, the imbalance in collagen-regulating genes of preeclamptic vessels was reproduced by treatment with neutrophils, tumor necrosis factor ␣, or reactive oxygen species. Chemotaxis studies with cultured cells revealed that MMP-1 promoted recruitment of neutrophils via vascular smooth muscle release of interleukin-8. Furthermore, MMP-1 induced vasoconstriction via protease-activated receptor-1, whose expression was significantly increased in omental arteries of preeclamptic women and in VSMCs co-cultured with neutrophils. Collectively, these findings disclose a novel role for MMP-1 as a mediator of vasoconstriction and vascular dysfunction in preeclampsia.

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“…Although platelets are activated by many stimuli, thrombin is the most potent of the platelet activators. 44 Platelets undergo shape change characterized by spikelike projections in response to thrombin followed by platelet aggregation by means of integrin binding von Willebrand factor and fibrinogen. 23 Thrombin also induces synthesis and secretion of adenosine diphosphate, endothelial platelet activating factor, serotonin, and thromboxane A2.…”

Section: Platelet and Endothelial Effectsmentioning

confidence: 99%

Thrombin physiology and pathophysiology

Licari

Kovacic²

2009

J Vet Emergen Crit Care

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Objectives -To review the role of thrombin in physiology and clinical disease and to discuss the pharmacology of antithrombosis. Data Sources -Original research articles, scientific reviews, textbooks. Human Data Synthesis -Thrombin and thrombin receptors are involved in a variety of physiologic and pathologic processes resulting in a great deal of interest in thrombin-related pharmacologic intervention. Veterinary Data Synthesis -Although there is little clinical research data available on thrombin specifically in veterinary patients, some of the original research on protease activated receptors was performed at veterinary institutions and many of the human molecular biology studies have been done on animals including dogs. Conclusion -Thrombin plays a significant role in coagulation, anticoagulation, and fibrinolysis. Antithrombotic treatment is focused on preventing thrombosis while maintaining hemostasis. Pharmaceutical agents are selected for the specific component of the coagulation pathway associated with a specific disease process, for a proven prophylactic benefit with procedures that carry a risk of thromboembolism, for rapidity of onset and ease of reversibility, for limited monitoring requirements, and for oral formulation and bioavailablity. Recent insight into other aspects of thrombin physiology presents an opportunity for pharmacologic intervention in a variety of other processes such as inflammation and sepsis, peripheral blood cell activation and chemotaxis, vascular endothelial and smooth muscle activity, cellular development and tissue repair, mitogenesis, neoplasia, and the function of nervous tissue following injury.

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Protease-Activated Receptors in Cardiovascular Diseases

Cited by 260 publications

References 78 publications

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

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

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

Thrombin physiology and pathophysiology

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