Plasmin-mediated Activation of Platelets Occurs by Cleavage of Protease-activated Receptor 4

Quinton, Todd M.; Kim, Soochong; Derian, Claudia K.; Jin, Jianguo; Kunapuli, Satya P.

doi:10.1074/jbc.m401431200

Cited by 109 publications

(83 citation statements)

References 26 publications

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“…5 and 8), kallikreins would promote the release of platelet endostatin and suppress the release of platelet vascular endothelial growth factor (51). The preferential activation of PAR 4 versus PAR 1 mirrors the action of plasmin on human platelets, wherein plasmin can both activate and disarm PAR 1 (60,61). Whether PAR 1 would be activated or disarmed by hK14 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Οικονομοπούλου

Hansen

Saifeddine

et al. 2006

Journal of Biological Chemistry

228

206

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Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs).Although thrombin is a recognized physiological activator of PAR 1 and PAR 4 , the endogenous enzymes responsible for activating PAR 2 in settings other than the gastrointestinal system, where trypsin can activate PAR 2 , are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR 1 , PAR 2 , and PAR 4 ; 2) PAR-dependent calcium signaling responses in cells expressing PAR 1 , PAR 2 , and PAR 4 and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR 4 -dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR 1 , PAR 2 , and PAR 4 and to disarm/inhibit PAR 1 . Although hK5 and -6 were also able to activate PAR 2 , they failed to cause PAR 4 -dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR 2 -mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR 1 , PAR 2 , and PAR 4 . Proteinase-activated receptors (PAR 1-4 )3 compose a unique family of four G-protein-coupled cell surface receptors for certain proteinases (1-9). Proteolytic cleavage within the extracellular N terminus reveals a tethered ligand that binds to the extracellular receptor domains to initiate cell signaling (5, 6, 9, 10). Proteinases that activate PARs include coagulation factors, enzymes from inflammatory cells, and proteinases from epithelial cells and neurons. These enzymes, generated and released during injury and inflammation, can cleave and activate PARs on many cell types from a variety of species (humans, rats, and mice) to regulate the critically important processes of hemostasis, inflammation, pain, and tissue repair. Other proteinases that cleave PARs downstream of the N-terminal tethered ligand sequence disable the receptors for further proteolytic activation, thus abrogating PAR signaling. It is of considerable interest to identify the proteinases that activate and/or disable PARs, in view of the emerging role that these receptors can play in diseases such as asthma, arthritis, inflammatory bowel disease, and cancer (5-7).In some systems, the proteinases that activate PARs have been established. For example, in the circulatory system, PAR 1 , PAR 3 , and PAR 4 are recognized physiological targets for thrombin (4), which does not efficiently acti...

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Section: Discussionmentioning

confidence: 99%

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Οικονομοπούλου

Hansen

Saifeddine

et al. 2006

Journal of Biological Chemistry

228

206

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“…As noted, multiple PARs also could enable responses to a wide repertoire of proteases (in addition to thrombin). Indeed, PAR-4 has been characterized variably as a cellular receptor for trypsin and plasmin (Sambrano et al, 2000;Quinton et al, 2004). In the case of plasmin, the kinetics of PAR-4 cleavage are relatively slow.…”

Section: Table 1 Structural and Functional Features Of Parsmentioning

confidence: 99%

The Cardiovascular Actions of Protease-Activated Receptors

Steinberg¹

2004

Mol Pharmacol

112

105

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Protease-activated receptors (PARs) comprise a family of G protein-coupled receptors with a unique proteolytic activation mechanism. PARs are activated by thrombin or other coagulation or inflammatory proteases formed at sites of tissue injury. PARs play a particularly important role in the pathogenesis of clinical disorders characterized by chronic inflammation or smoldering activation of the coagulation cascade. Individual PARs have been linked to the regulation of a broad range of cellular functions. Recent studies identify PAR family members in the vasculature (including within atherosclerotic lesions) and in the heart. Here, PAR-triggered responses contribute to vasoregulation and influence cardiac electrical and mechanical activity. PAR activation also is linked to structural remodeling of the vasculature and the myocardium. This review focuses on the cardiovascular actions of PARs that play a role in normal cardiovascular physiology and that are likely to contribute to cardiovascular diseases.Thrombin was first identified as a trypsin-like serine protease produced at sites of vessel injury or tissue damage, which plays a key role in blood coagulation by converting fibrinogen to fibrin (the fibrous matrix of blood clots). However, early studies exposed an additional effect of thrombin to promote platelet aggregation, even in the absence of any other coagulation factors. The molecular basis for the cellular actions of thrombin, distinct from its role in clot formation, was first elucidated by the Coughlin laboratory with the cloning of PAR-1 in 1991 (Coughlin, 2000). Subsequent research identified PAR-1 as a prototype of a family of related PARs that have important nonhemostatic functions in development, play a role in tumor biology, and orchestrate a series of highly regulated responses that are integral to the inflammatory response and are vital for normal tissue repair. The broad scope of cellular processes regulated by PARs is evident from the recent excellent reviews that consider roles for PARs in inflammation and wound healing, vasoregulation, angiogenesis, atherosclerosis, gastrointestinal disorders, pain perception by sensory neurons, airway hyper-reactivity, and inflammatory pulmonary diseases (Vergnolle, 2000;Macfarlane et al., 2001;Vergnolle et al., 2001;Major et al., 2003;Ossovskaya and Bunnett, 2004). PARs also exert a wide range of cardiovascular actions. Most of the published literature has focused on PAR-mediated action in platelets and the vasculature. Here, PARs are critical for normal hemostasis and contribute to the pathogenesis of vascular disorders characterized by chronic inflammation or smoldering activation of the coagulation cascade (including vascular atherosclerosis). However, there is recent evidence that PARs also exert direct effects on the heart that lead to changes in contractile performance and structural remodeling of ventricular cardiomyocytes. This review briefly summarizes the pharmacological properties of the four known PAR family members before focusing on re...

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“…2,[25][26][27][28] Plasmin either activates or disarms PAR1, 6,29,30 whereas it inactivates PAR2 and activates PAR4. 31,32 The activated protein C (APC) has been shown to activate PAR1 and PAR2, [33][34][35] although its functional role still remains controversial. 36 In the following sections, I would like to discuss the role of PARs in regulating the vascular functions and in the pathophysiology of vascular diseases, with some focus on thrombin and its major receptor PAR1.…”

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confidence: 99%

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Hirano

2007

ATVB

137

121

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Abstract-Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. (Arterioscler Thromb Vasc Biol. 2007;27:27-36.)

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Plasmin-mediated Activation of Platelets Occurs by Cleavage of Protease-activated Receptor 4

Cited by 109 publications

References 26 publications

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Proteinase-activated Receptors, Targets for Kallikrein Signaling

The Cardiovascular Actions of Protease-Activated Receptors

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

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