Proteinase-activated receptor 1 (PAR-1) and cell apoptosis

Flynn, Andrew N.; Buret, André G.

doi:10.1023/b:appt.0000045784.49886.96

Cited by 67 publications

(63 citation statements)

References 89 publications

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“…Under these circumstances, PAR-1 has been linked to both pro-and anti-apoptotic effects depending on the cell type and the experimental conditions (46). For example, activation of PAR-1 by thrombin can either induce or inhibit apoptosis in cultured neurons and astrocytes (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…Diverse and interconnected signaling molecules are known to be involved in apoptosis including NF-B, mitogen-activated protein (MAP) kinases, phosphatidylinositide 3-kinase (PI3K), and tyrosine kinases (44,46,56,57). In the current study, we focused on two additional signaling molecules modulated by leukocyte elastase that lie downstream of PAR-1.…”

Section: Discussionmentioning

confidence: 99%

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Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Suzuki

Moraes

Vachon

et al. 2005

Am J Respir Cell Mol Biol

123

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Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1-activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1-dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Suzuki

Moraes

Vachon

et al. 2005

Am J Respir Cell Mol Biol

123

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“…Thrombin stimulates endothelial cells to reconstruct the cytoskeleton, thus altering the cell form and degrading intercellular adhesion mediated by VE-cadherin [38]. Thrombin also induces the apoptosis of endothelial cells [6][7][8]. These responses decrease endothelial permeability, leading to thrombin localization under endothelial cells.…”

Section: Blood Vesselsmentioning

confidence: 99%

“…After receptors for thrombin were identified on platelets and endothelial cells, researchers began to intensively examine the effects of thrombin on cells [5]. Thrombin increases the permeability of the endothelial cell layer and induces apoptosis of endothelial cells [6][7][8]. These functions play an important role in wound healing in conjunction with hemostasis.…”

Section: Introductionmentioning

confidence: 99%

Bidirectional Pathologic Effects of Thrombin

Hidai¹

2018

Anat Physiol

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Hemostasis is an essential reaction in organisms with circulatory systems. To stop bleeding as soon as possible, reactions of the coagulation system proceed rapidly and are regulated by positive feedback loops. However, coagulation can be harmful when induced at inappropriate sites, potentially resulting in local thromboembolisms in vital organs such as the heart and brain and systemic microthrombi in conditions such as disseminated intravascular coagulopathy. Increasingly, reports indicate that coagulation-related factors can cause serious diseases without obvious thromboembolism-associated ischemia, for example, atherosclerosis and Alzheimer disease. Thrombin is an essential coagulation factor that can also cause tissue injury, particular to endothelial cells. However, thrombin can also function as a tissue-protective factor depending on conditions. Endothelial protein C receptor (EPCR) and protease-activated receptors (PARs) regulate thrombin activity, but many details regarding the mechanisms remain unknown. This short review summarizes the bidirectional effects of thrombin signaling via EPCR and PAR1 and discusses points relevant to translating the tissue-protective effects of thrombin into clinical benefits.

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“…In the absence of Integrilin and Aggrastat, caspase-3 activation induced by thrombin and A23187 is primarily triggered by pro-apoptotic signal transduction through proteinase-activated receptors (PAR) 7,12 and by calcium mobilization/overloading, 8 respectively; GPIIbIIIa integrins are then secondarily activated by inside-out signaling, bind plasma-and/or platelet-derived fibrinogen and/or von Willebrand factor (VWF) 1,2 and transmit pro-apoptotic outside-in signaling further promoting thrombin-or A23187-induced caspase-3 activation. In the presence of Integrilin or Aggrastat, on the other hand, the GPIIbIIIa antagonist inhibits caspase-3 activation induced by thrombin or A23187, attenuating transmission of proapoptotic outside-in signaling through active GPIIbIIIa by inhibiting fibrinogen/VWF binding and/or preventing conversion of GPIIbIIIa to a fully active conformation.…”

mentioning

confidence: 99%

The GPIIbIIIa antagonist drugs eptifibatide and tirofiban do not induce activation of apoptosis executioner caspase-3 in resting platelets but inhibit caspase-3 activation in platelets stimulated with thrombin or calcium ionophore A23187

Leytin¹,

Mutlu²,

Mykhaylov³

et al. 2009

Haematologica

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The GPIIbIIIa antagonist drugs eptifibatide and tirofiban do not induce activation of apoptosis executioner caspase-3 in resting platelets but inhibit caspase-3 activation in platelets stimulated with thrombin or calcium ionophore A23187Platelet surface receptor, glycoprotein (GP) IIbIIIa (integrin αIIbβ3), mediates platelet aggregation and plays a key role in hemostasis and thrombosis. 1,2Numerous GPIIbIIIa antagonists have been designed and tested as inhibitors of platelet aggregation.3 Two of these antagonists, eptifibatide (Integrilin) and tirofiban (Aggrastat), are approved by the US Food and Drug Administration (FDA) for clinical use for preventing and treating thrombotic complications in patients undergoing percutaneous coronary intervention and in patients with acute coronary syndromes.4 It has been reported, however, that some GPIIbIIIa antagonists, such as orbofiban and xemilofiban, promote apoptosis in cardiomyocytes by activation of the apoptosis executioner caspase-3, 5 raising the possibility that platelets also may be susceptible to pro-apoptotic effects of Integrilin and Aggrastat.Over the past decade it has been well-documented by us and others that apoptosis occurs not only in nucleated cells but also in anucleated platelets stimulated with thrombin, calcium ionophores, very high shear stresses and platelet storage (see references in [6][7][8] ). It has been further reported that platelet activation and apoptosis may be induced by different mechanisms and/or require different levels of triggering stumuli.9,10 Recently, we have shown that injection of anti-GPIIb antibody induced caspase-3 activation in mouse platelets, 11 suggesting that direct GPIIbIIIa-mediated pro-apoptotic signaling is able to trigger caspase-3 activation within platelets.The current study aimed to examine, for the first time, the effect of Integrilin and Aggrastat on caspase-3 activation in human platelets. We studied the effects of Integrilin and Aggrastat on caspase-3 activation in resting platelets which express GPIIbIIIa receptors in their nonactive (closed) conformation, and in platelets stimulated with thrombin and calcium ionophore A23187, which induce transition of GPIIbIIIa receptors into active (open) conformation. Table 1A shows that treatment of resting platelets with Integrilin and Aggrastat did not affect caspase-3 activation (p>0.05). In contrast, a 2.3-2.7-fold increase in caspase-3 activation was observed in platelets after thrombin and A23187 stimulation (Table 1B and C, p<0.01). However, when platelets were preincubated with Integrilin and Aggrastat before agonist treatment, these drugs significantly inhibited agonist-induced caspase-3 activation ( Figure 1 and Table 1B and C, p<0.05).The fact that Integrilin and Aggrastat do not promote caspase-3 activation in unstimulated platelets (Table 1A) suggests that these GPIIbIIIa antagonists do not induce transmission of pro-apoptotic transmembrane signals inside platelets through inactive GPIIbIIIa integrin. They also do not activate caspase-3 directly by inte...

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Proteinase-activated receptor 1 (PAR-1) and cell apoptosis

Cited by 67 publications

References 89 publications

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Bidirectional Pathologic Effects of Thrombin

The GPIIbIIIa antagonist drugs eptifibatide and tirofiban do not induce activation of apoptosis executioner caspase-3 in resting platelets but inhibit caspase-3 activation in platelets stimulated with thrombin or calcium ionophore A23187

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