Platelet Death.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-40-sci-40
Author(s):  
Emma C. Josefsson ◽  
Simone Schoenwaelder ◽  
Michael White ◽  
Matthew Goschnick ◽  
Andrew W. Roberts ◽  
...  
Keyword(s):  
Cell Death ◽  
Cultured Cells ◽  
Preliminary Evidence ◽  
Human Platelets ◽  
Mitochondrial Damage ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Abstract Human platelets exhibit a circulating lifespan of ~10 days, mouse platelets ~5 days. This finite existence is circumscribed by members of the Bcl-2 family of proteins, which control the intrinsic apoptosis pathway. Pro-survival Bcl-xL is the critical regulator of platelet lifespan, functioning to keep pro-death Bak and Bax in check, thereby maintaining platelet viability. After 5–10 days in the circulation, platelets not consumed in hemostatic processes initiate a Bak and Bax-dependent cell death program and clearance from the bloodstream. Mutations in Bcl-xL reduce platelet lifespan in a dose-dependent fashion, while deletion of Bak and Bax extend it. Studies with the BH3 mimetic compound ABT-737, which inhibits pro-survival Bcl-xL, have shown that platelets induced to undergo cell death in vitro exhibit many of the hallmarks of apoptosis in nucleated cells, including mitochondrial damage, caspase activation and externalization of membrane phosphatidylserine (PS). Whether any of these features occur during physiological platelet clearance remains unclear. Certainly, mitochondrial damage can reduce the recovery of transfused platelets, but whether PS – which is known to promote the pro-coagulant activity of agonist-activated platelets – also acts as a clearance signal for dying platelets in vivo is yet to be established. Conversely, Bak and Bax may play a role in mediating PS exposure triggered by activation. Supporting the idea that there may be crosstalk between classical platelet signaling pathways and the intrinsic apoptosis pathway is recent evidence that platelet agonists can also activate caspases. Intriguingly, elements of the intrinsic pathway may also contribute to the generation of platelets by megakaryocytes. Several groups have demonstrated that megakaryocytes contain activated caspases and that their inhibition can block platelet shedding by cultured cells. Preliminary evidence we have generated suggests that Bcl-2 family proteins may be required for platelet production in vivo. Thus, it appears that there is much to be understood about the role of the intrinsic apoptosis pathway in the regulation of platelet biogenesis, function, and death.

scholarly journals The role of BH3-only proteins in apoptosis within the ovary

Reproduction ◽  
2015 ◽  
Vol 149 (2) ◽  
pp. R81-R89 ◽  
Author(s):  
Karla J Hutt
Keyword(s):  
Cell Death ◽  
Endocrine Function ◽  
Environmental Toxicants ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Bcl2 Family ◽  
Intrinsic Apoptosis Pathway

BH3-only proteins are pro-apoptotic members of the BCL2 family that play pivotal roles in embryonic development, tissue homeostasis and immunity by triggering cell death through the intrinsic apoptosis pathway. Recentin vitroandin vivostudies have demonstrated that BH3-only proteins are also essential mediators of apoptosis within the ovary and are responsible for the initiation of the cell death signalling cascade in a cell type and stimulus-specific fashion. This review gives a brief overview of the intrinsic apoptosis pathway and summarise the roles of individual BH3-only proteins in the promotion of apoptosis in embryonic germ cells, oocytes, follicular granulosa cells and luteal cells. The role of these proteins in activating apoptosis in response to developmental cues and cell stressors, such as exposure to chemotherapy, radiation and environmental toxicants, is described. Studies on the function of BH3-only proteins in the ovary are providing valuable insights into the regulation of oocyte number and quality, as well as ovarian endocrine function, which collectively influence the female reproductive lifespan and health.

scholarly journals Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity

2021 ◽  
Vol 7 (25) ◽  
pp. eabf8577
Author(s):  
Hin Chu ◽  
Huiping Shuai ◽  
Yuxin Hou ◽  
Xi Zhang ◽  
Lei Wen ◽  
...  
Keyword(s):  
Disease Severity ◽  
Lung Damage ◽  
Intrinsic Apoptosis ◽  
Highly Pathogenic ◽  
In Vivo Models ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Induced Apoptosis

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R–like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2– and SARS-CoV–induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2–inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.

scholarly journals Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Christopher Platen ◽  
Stephan Dreschers ◽  
Jessica Wappler ◽  
Andreas Ludwig ◽  
Stefan Düsterhöft ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Infections ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Intrinsic Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

scholarly journals Cell death following the loss of ADAR1 mediated A-to-I RNA editing is not effected by the intrinsic apoptosis pathway

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Carl R. Walkley ◽  
Benjamin T. Kile
Keyword(s):  
Cell Death ◽  
Rna Editing ◽  
Rna Structure ◽  
Fetal Liver ◽  
Loss Of Function ◽  
Intrinsic Apoptosis ◽  
Triple Mutant ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

AbstractModifications of RNA, collectively termed as the epitranscriptome, are widespread, evolutionarily conserved and contribute to gene regulation and protein diversity in healthy and disease states. There are >160 RNA modifications described, greatly exceeding the number of modifications to DNA. Of these, adenosine-to-inosine (A-to-I) RNA editing is one of the most common. There are tens of thousands of A-to-I editing sites in mouse, and millions in humans. Upon translation or sequencing an inosine base is decoded as guanosine, leading to A-to-G mismatches between the RNA and DNA. Inosine has different base pairing properties to adenosine and as a result editing not only alters the RNA code but can also change the RNA structure. In mammals A-to-I editing is performed by ADAR1 and ADAR2. A feature of murine loss of function ADAR1 alleles is cell death and a failure to survive embryogenesis. Adar1−/− and editing deficient (Adar1E861A/E861A) mice die between E11.75–13.5 of failed hematopoiesis. Strikingly this phenotype is rescued by the deletion of the cytosolic dsRNA sensor MDA5 or its downstream adaptor MAVS, a mechanism conserved in human and mouse. Current literature indicates that the loss of ADAR1 leads to cell death via apoptosis, yet this has not been genetically established. We report that blockade of the intrinsic (mitochondrial) apoptosis pathway, through the loss of both BAK and BAX, does not rescue or modify the cellular phenotype of the fetal liver or extend the lifespan of ADAR1 editing deficient embryos. We had anticipated that the loss of BAK and BAX would rescue, or at least significantly extend, the gestational viability of Adar1E861A/E861A embryos. However, the triple mutant Adar1E861A/E861ABak−/−Bax−/− embryos that were recovered at E13.5 were indistinguishable from the Adar1E861A/E861A embryos with BAK and BAX. The results indicate that cell death processes not requiring the intrinsic apoptosis pathway are triggered by MDA5 following the loss of ADAR1.

Megakaryocytes Possess a Functional Intrinsic Apoptosis Pathway That Must Be Restrained In Order to Survive and Produce Platelets

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 550-550
Author(s):  
Emma C Josefsson ◽  
Chloé James ◽  
Katya J Henley ◽  
Marlyse A Debrincat ◽  
Kelly L Rogers ◽  
...  
Keyword(s):  
Life Span ◽  
Intrinsic Apoptosis ◽  
Intrinsic Pathway ◽  
Apoptosis Pathway ◽  
Platelet Production ◽  
Apoptotic Death ◽  
Intrinsic Apoptosis Pathway ◽  
Bh3 Mimetic ◽  
Platelet Formation

Abstract Abstract 550 It is widely held that megakaryocytes undergo a specialized form of apoptosis in order to shed platelets. Conversely, it is also believed that a range of insults including chemotherapeutic agents, autoantibodies and viruses, cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. However, the apoptotic pathways that megakaryocytes possess, and the role they play in survival and platelet production are ill-defined. We recently demonstrated that platelets contain a classical intrinsic mitochondrial apoptosis pathway that regulates their life span in vivo. The key components of this pathway are the Bcl-2 family pro-survival protein Bcl-xL, and pro-death Bak and Bax. Deletion of Bak and Bax—the gatekeepers of the intrinsic pathway—blocks platelet apoptosis in response to genetic mutation or pharmacological insult, and significantly extends circulating platelet life span. To elucidate the role of the intrinsic apoptosis pathway in megakaryocytes, we generated both hematopoietic- and megakaryocyte lineage-specific deletions of Bak and Bax in mice. Surprisingly, we found that the ability of Bak−/−Bax−/− animals to produce platelets, both at steady state and under conditions of thrombopoietic stress, was unperturbed. Megakaryocyte numbers, morphology and ploidy were normal. Bak−/−Bax−/− megakaryocytes cultured in vitro showed no impairment of pro-platelet formation. Thus, classical intrinsic apoptosis is not required by megakaryocytes for the process of platelet shedding. Given that in platelets, Bak and Bax must be kept in check to maintain survival, we reasoned that the same might be true of megakaryocytes. If so, then it would be expected that one or more members of the Bcl-2 family of pro-survival proteins restrain Bak and Bax. Since Bcl-xL fulfills this role in platelets, we generated mice lacking Bcl-xL in the megakaryocyte lineage. Platelet counts in Bcl-xPf4CΔ/Pf4CΔ animals were approximately 2% of those observed in Bcl-xfl/fl littermates. Platelet life span was reduced to 5 hours, versus 5 days in controls, underscoring the requirement for Bcl-xL in mediating platelet survival. In addition, reticulated platelet analyses combined with mathematical modeling suggested that Bcl-xPf4CΔ/Pf4CΔ mice had an underlying platelet production defect. Further examination revealed that megakaryocyte numbers were significantly increased in both the bone marrow and spleen of Bcl-xPf4CΔ/Pf4CΔ animals relative to Bcl-xfl/fl controls. Megakaryocyte progenitor numbers were doubled, and serum TPO levels were dramatically reduced, indicating a megakaryocyte compartment under considerable thrombopoietic stress. In vitro cultures confirmed that Bcl-xPf4CΔ/Pf4CΔ megakaryocytes were able to develop and mature. Strikingly, however, at the point of pro-platelet formation, they underwent an abortive attempt to generate extensions and died. Death was accompanied by a dramatic increase in apoptotic effector caspase activity. This suggested that, like platelets, megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained in order to survive, and that Bcl-xL is the factor that does so during pro-platelet formation and platelet shedding. To establish whether Bak and Bax can mediate megakaryocyte death, we examined the effect on mature wild type megakaryocytes of three pharmacological agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and a BH3 mimetic that inhibits Bcl-xL, Bcl-2 and Bcl-w. All three triggered mitochondrial damage, caspase activation and cell death. Remarkably, genetic deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and the BH3 mimetic, but not staurosporine. Our results demonstrate that megakaryocytes can undergo classical Bak- and Bax-mediated apoptotic death. They do not activate the intrinsic pathway to facilitate platelet shedding, rather, the opposite is true: they must restrain it in order to survive and generate platelets. These findings offer a potential mechanism for the death of megakaryocytes in response to insults such as cancer chemotherapy. They also suggest that additional megakaryocyte cell death pathways remain to be elucidated. Disclosures: Roberts: Abbott: Research Funding.

scholarly journals Pro-apoptotic caspase deficiency reveals a cell-extrinsic mechanism of NK cell regulation

2021 ◽  
Author(s):  
Tayla M. Olsen ◽  
Wei Hong Tan ◽  
Arne C. Knudsen ◽  
Anthony Rongvaux
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Nk Cell ◽  
Apoptotic Cell ◽  
Type I ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
A Cell

AbstractRegulated cell death is essential for the maintenance of cellular and tissue homeostasis. In the hematopoietic system, genetic defects in apoptotic cell death generally produce the accumulation of immune cells, inflammation and autoimmunity. In contrast, we found that genetic deletion of caspases of the mitochondrial apoptosis pathway reduces natural killer (NK) cell numbers and makes NK cells functionally defective in vivo and in vitro. Caspase deficiency results in constitutive activation of a type I interferon (IFN) response, due to leakage of mitochondrial DNA and activation of the cGAS/STING pathway. The NK cell defect in caspase-deficient mice is independent of the type I IFN response, but the phenotype is partially rescued by cGAS or STING deficiency. Finally, caspase deficiency alters NK cells in a cell-extrinsic manner. Type I IFNs and NK cells are two essential effectors of antiviral immunity, and our results demonstrate that they are both regulated in a caspase-dependent manner. Beyond caspase-deficient animals, our observations may have implications in infections that trigger mitochondrial stress and caspase-dependent cell death.

scholarly journals Aviculin Isolated from Lespedeza cuneata Induce Apoptosis in Breast Cancer Cells through Mitochondria-Mediated Caspase Activation Pathway

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1708 ◽  
Author(s):  
Dahae Lee ◽  
Yong Hoon Lee ◽  
Kwang Ho Lee ◽  
Bum Soo Lee ◽  
Akida Alishir ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Underlying Mechanism ◽  
Intrinsic Apoptosis ◽  
Lespedeza Cuneata ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Mcf 7

The global incidence of breast cancer has increased. However, there are many impediments to the development of safe and effective anticancer drugs. The aim of the present study was to evaluate the effect of aviculin isolated from Lespedeza cuneata (Dum. Cours.) G. Don. (Fabaceae) on MCF-7 human breast cancer cells and determine the underlying mechanism. Using the bioassay-guided isolation by water soluble tetrazolium salt (WST-1)-based Ez-Cytox assay, nine compounds (four lignan glycosides (1–4), three flavonoid glycosides (5–7), and two phenolic compounds (8 and 9)) were isolated from the ethyl acetate (EA) fraction of the L. cuneata methanolic extract. Of these, aviculin (2), a lignan glycoside, was the only compound that reduced metabolic activity on MCF-7 cells below 50% (IC50: 75.47 ± 2.23 μM). The underlying mechanism was analyzed using the annexin V Alexa Fluor 488 binding assay and Western blotting. Aviculin (2) was found to induce apoptotic cell death through the intrinsic apoptosis pathway, as indicated by the increased expression of initiator caspase-9, executioner caspase-7, and poly (ADP-ribose) polymerase (PARP). Aviculin (2)-induced apoptotic cell death was accompanied by an increase in the Bax/Bcl-2 ratio. These findings demonstrated that aviculin (2) could induce breast cancer cell apoptosis through the intrinsic apoptosis pathway, and it can therefore be considered an excellent candidate for herbal treatment of breast cancer.

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