Platelet senescence and phosphatidylserine exposure

Dasgupta, Swapan; Argaiz, Eduardo R.; Mercado, Jose Emmanel Chedid; Maul, Hector Omar Elizondo; Garza, Jorge; Enríquez, Ana Bety; Abdel-Monem, Hanan; Prakasam, Anthony; Andreeff, Michael; Thiagarajan, Perumal

doi:10.1111/j.1537-2995.2010.02676.x

Cited by 60 publications

(57 citation statements)

References 34 publications

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“…25,32 Therefore, we investigated apoptosis pathways after exposure to platelet agonists or BCL2 inhibition. Exposure to ABT-737 induced loss of MMP (Figure 2A,C), release of cytochrome c ( Figure 2B-C), and caspase cleavage ( Figure 2C-D), in agreement with activation of the intrinsic apoptotic pathway.…”

Section: Bcl2/x L Inhibition But Not Platelet Activation Induces Apmentioning

confidence: 99%

“…Some studies have addressed this question by comparing platelet activation and apoptosis. [23][24][25] Here we investigated the effects of BCL2 inhibition on both platelet apoptosis and activation. We demonstrate that both processes are clearly distinguishable because apoptosis occurs slowly over hours and results in biochemical and ultrastructural changes that are clearly different from those seen during the more rapid process of agonist-induced activation, which occurs within minutes.…”

Section: Introductionmentioning

confidence: 99%

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BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

Vogler

Hamali

Sun

et al. 2011

Blood

164

147

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Apoptosis in megakaryocytes results in the formation of platelets. The role of apoptotic pathways in platelet turnover and in the apoptotic-like changes seen after platelet activation is poorly understood. ABT-263 (Navitoclax), a specific inhibitor of antiapoptotic BCL2 proteins, which is currently being evaluated in clinical trials for the treatment of leukemia and other malignancies, induces a doselimiting thrombocytopenia. In this study, the relationship between BCL2/BCL-X L inhibition, apoptosis, and platelet activa- IntroductionAll nucleated cells in multicellular organisms are genetically programmed to undergo apoptosis to remove unnecessary or damaged cells from the whole organism. This program has been recognized as the central mechanism of platelet production from megakaryocytes. 1 However, the role of apoptosis in anuclear, mature platelets is less well characterized, with apoptotic-like changes seen in both aging platelets and in the formation of procoagulant microparticles after agonist stimulation.Two main pathways lead to the execution of apoptosis: the extrinsic and the intrinsic (or mitochondrial) pathways. Both converge into the activation of caspases, which are proteases that cleave Ͼ 500 cellular targets and induce typical morphologic changes associated with apoptosis in nucleated cells. A critical step in the intrinsic pathway is the loss of mitochondrial membrane potential (MMP) and the release of cytochrome c into cytosol, where it triggers the activation of caspase-9. Therefore, the release of cytochrome c from mitochondria needs to be tightly regulated: a function that is fulfilled by the BCL2 protein family, which consists of proapoptotic and antiapoptotic members that promote or block the release of cytochrome c, respectively. 2,3 The proapoptotic family members BAX and BAK play an essential role in directly mediating the release of cytochrome c by forming a pore in the outer mitochondrial membrane. Antiapoptotic BCL2 proteins, including BCL2, BCL-X L , BCL-w, MCL1, and BCL2A1, prevent the activation of BAX and BAK. Besides their function in regulating mitochondrial cytochrome c release, BCL2 proteins have also been implicated in the regulation of intracellular calcium homeostasis at the endoplasmic reticulum (ER), possibly by interacting with inositol triphosphate receptors. 4,5 Because of their key role, the antiapoptotic BCL2 proteins are attractive targets for anticancer therapy, with several small molecule inhibitors currently in preclinical testing or early clinical trials. 6,7 Among these, the most promising and specific inhibitors are ABT-263 (Navitoclax) and 9 ABT-737 shows promising antitumor activity in animal models of leukemia and lymphoma. A related compound, ABT-263, is metabolically more stable and currently in phase 1 and 2 clinical trials for leukemia and other malignancies. 10 Both compounds have often been regarded as interchangeable because they bind with high affinity to BCL2, BCL-X L , and BCL-w but do not inhibit MCL1 or BCL2A1. 11 Early results from the clinica...

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Section: Bcl2/x L Inhibition But Not Platelet Activation Induces Apmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

Vogler

Hamali

Sun

et al. 2011

Blood

164

147

View full text Add to dashboard Cite

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“…30,33,34,44,45 To determine the role of caspase-9 in this process, we treated platelets from wild-type, Bak Ϫ/Ϫ Bax Ϫ/Ϫ , or Casp9 Ϫ/Ϫ FLC-reconstituted mice with ABT-737 for 90 minutes and measured apoptotic caspase activity, and ATP levels (an indicator of mitochondrial function). In wild-type platelets, a strong dose-dependent activation of caspase-9, and of the effector caspases-3 and -7, was observed ( Figure 2B).…”

Section: Caspase-9 Mediates Platelet Apoptosis and Ps Externalizationmentioning

confidence: 99%

“…29 Although it is now well established that Bcl-x L and Bak regulate platelet survival and lifespan at steady state, [30][31][32][33][34] the requirement for caspases in mediating platelet turnover is unclear. Certainly, induction of platelet apoptosis results in caspase activation, and caspase inhibition can block PS exposure, 33 but the physiologic significance of this phenomena remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

White

Schoenwaelder

Josefsson

et al. 2012

Blood

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Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phospha- IntroductionApoptotic caspases are a family of aspartate-specific cysteinyl proteases that are activated during, and facilitate the execution of, programmed cell death. They cleave a range of cellular substrates, thereby causing the morphologic and biochemical signatures of apoptosis, such as DNA fragmentation, membrane blebbing, and phosphatidylserine (PS) externalization. In addition to their role in cell death, apoptotic caspases have been ascribed an increasing number of functions. These include critical roles in the differentiation of erythroid cells, 1 osteoblasts, 2 keratinocytes, 3 lens fiber cells, 4 skeletal muscle, 5 and embryonic stem (ES) cells. 6 Apoptotic caspases have also been suggested to regulate B-lymphocyte proliferation, 7 HSC quiescence, 8 activation of microglia, 9 and the reprogramming of fibroblasts into iPS (induced pluripotent stem cells). 10 There are 2 pathways to apoptosis, the intrinsic and the extrinsic. Both ultimately converge on the apoptotic effector caspases, caspase-3 and caspase-7. The intrinsic (or mitochondrial) apoptosis pathway is regulated by the interaction between Bcl-2 family proteins, which are divided into prosurvival and prodeath subsets. The critical mediators of the pathway are the prodeath proteins Bak and Bax, which, in viable cells are restrained by one or more of the 5 prosurvivals: Bcl-2, Bcl-x L , Mcl-1, Bcl-w, and A1. In response to apoptotic signals such as DNA damage or growth factor deprivation, a third group of Bcl-2 family members, the "BH3-only" proteins, trigger the activation of Bak and Bax. 11,12 Active Bak and Bax cause mitochondrial outer membrane permeabilization (MOMP), which allows apoptogenic factors, including cytochrome c, to enter the cytosol. 13 Cytochrome c interacts with the scaffolding protein Apaf-1. Subsequently, the initiator caspase, caspase-9, is recruited to the cytochrome c/Apaf-1 complex to form the apoptosome. 14 This leads to the activation of caspase-9 and triggering of the caspase cascade. The importance of the caspas...

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“…Cytochrome c (Cyt-c) was shown to redistribute from mitochondria to the cytosol during apoptosis in cells. The measurement of Cyt-c release in platelets was performed with the human Cyt-c ELISA Kit (eBioscience, Germany) as described previously (Dasgupta et al, 2010;Cevik et al, 2013). Platelets were resuspended with lysis buffer and then centrifuged at 18,000 × g for 10 min.…”

Section: Measurement Of Camentioning

confidence: 99%

Tumor necrosis factor-alpha induced caspase-3 activation-related iNOS gene expression in ADP-activated platelets

Çevik¹,

Adiguzel²,

Baykal³

et al. 2017

Turk J Biol

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Platelets are sensitive cells and are easily activated by different stimulants in the circulation system. It is known that tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine and plays a role in inflammation. The role of TNF-α in the apoptotic process in blood platelets is unknown. In order to study the formation of apoptosis in platelets after incubation with TNF-α and/or ADP, several biomarkers were chosen: phosphatidylserine (PS) exposure and P-selectin binding; cGMP, Cyt-c, and Ca 2+ levels and NOS activation; and gene and protein expression of caspase-3 and iNOS. Platelets were incubated with 100 pg/mL TNF-α and/or 50 mM iNOS specific inhibitor, such as at 1400 W for 1 h at 37 °C in the presence of 5 µM ADP. According to the results, the levels of PS exposure and P-selectin binding were significantly higher in TNF-α + ADP platelets, which decreased with the addition of 1400 W. A significant induction in cGMP, Cyt-c, and Ca 2+ levels was observed in platelets treated with TNF-α + ADP. On the other hand, the upregulation of the apoptotic gene caspase-3 and iNOS expression levels in TNF-α-treated and ADP-activated platelets was significantly reversed with the addition of 1400 W. These data demonstrate that TNF-α promotes iNOS expression through caspase-3 stimulation in human platelets, and its concomitance leads to the triggering of apoptosis-mediated inflammation upon platelet activation.

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Platelet senescence and phosphatidylserine exposure

Cited by 60 publications

References 34 publications

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

Tumor necrosis factor-alpha induced caspase-3 activation-related iNOS gene expression in ADP-activated platelets

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