Prostacyclin prevents nitric oxide‐induced megakaryocyte apoptosis

Pozner, Raúl; Negrotto, Soledad; D’Atri, Lina Paola; Kotler, Mónica Lidia; Lazzari, M.A.; Gómez, Ricardo Martín; Schattner, Mirta

doi:10.1038/sj.bjp.0706200

Cited by 18 publications

(11 citation statements)

References 43 publications

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“…Increased expression of the PKA regulatory subunit RII has been reported in human CD34 + -derived MKs [27]. Increased cAMP has been found to delay apoptosis of CD34 + stem cells and MKs [28,29]. cAMP also increases expression of the chemokine receptor CXCR4, which augments the ability of CD34 + cells to transmigrate to the endothelium and to adhere to stroma [30].…”

Section: Discussionmentioning

confidence: 99%

Differential roles of cAMP and cGMP in megakaryocyte maturation and platelet biogenesis

Begonja

Gambaryan

Schulze

et al. 2013

Experimental Hematology

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The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) regulate the activity of protein kinase A (PKA) and protein kinase G (PKG), respectively. This process helps maintain circulating platelets in a resting state. Here we studied the role of cAMP and cGMP in the regulation of megakaryocyte (MK) differentiation and platelet formation. Cultured, platelet-producing MKs were differentiated from fetal livers harvested from 13.5 days postcoital mouse embryos. MK development was accompanied by a dramatic increase in cAMP production and expression of soluble guanylate cyclase, PKG, and PKA as well as their downstream targets vasodilator-stimulated phosphoprotein (VASP) and MENA. Stimulation of prostaglandin E1 receptor/adenylyl cyclase or soluble guanylate cyclase/PKG in cultured MKs increased VASP phosphorylation, indicating that these components share a common signaling pathway. To dissect out the role of cyclic nucleotides in MK differentiation, cAMP/PKA and cGMP/PKG signaling were alternately blocked in cultured MKs. Down-regulation of cAMP pathway effectors decreased MK numbers and ploidy. Notably, cGMP levels increased at the beginning of MK development and returned to basal levels in parallel with MK maturation. However, inhibition of cGMP pathway effectors had no effect on MK development. In addition, platelet release from mature MKs was enhanced by cGMP and inhibited by cAMP. Our data suggest that cAMP plays an important role in MK differentiation, while cAMP and cGMP have opposite effects on platelet production. Identifying the signaling pathways that underpin MK development and proplatelet formation will provide greater insights into thrombopoiesis and may potentially yield useful therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Differential roles of cAMP and cGMP in megakaryocyte maturation and platelet biogenesis

Begonja

Gambaryan

Schulze

et al. 2013

Experimental Hematology

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“…Mock-infected controls contained supernatants of Vero cells instead of JUNV. After washing, UV-irradiated JUNV-, JUNV- or mock-infected CD34 + cells were cultured in Iscove's Modified Dulbecco's Medium (IMDM, HyClone) containing 2 mM glutamine, 5% human serum (obtained by re-calcification of citrated platelet-free plasma), 25 ng/ml TPO and antibiotics (growth medium) at 37°C in a humidified atmosphere with 5% CO 2 [50] . Fresh TPO (25 ng/ml) was added at day seven.…”

Section: Methodsmentioning

confidence: 99%

Junín Virus Infection of Human Hematopoietic Progenitors Impairs In Vitro Proplatelet Formation and Platelet Release via a Bystander Effect Involving Type I IFN Signaling

et al. 2010

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Argentine hemorrhagic fever (AHF) is an endemo-epidemic disease caused by Junín virus (JUNV), a member of the arenaviridae family. Although a recently introduced live attenuated vaccine has proven to be effective, AHF remains a potentially lethal infection. Like in other viral hemorrhagic fevers (VHF), AHF patients present with fever and hemorrhagic complications. Although the causes of the bleeding are poorly understood, impaired hemostasis, endothelial cell dysfunction and low platelet counts have been described. Thrombocytopenia is a common feature in VHF syndromes, and it is a major sign for its diagnosis. However, the underlying pathogenic mechanism has not yet been elucidated. We hypothesized that thrombocytopenia results from a viral-triggered alteration of the megakaryo/thrombopoiesis process. Therefore, we evaluated the impact of JUNV on megakaryopoiesis using an in vitro model of human CD34+ cells stimulated with thrombopoietin. Our results showed that CD34+ cells are infected with JUNV in a restricted fashion. Infection was transferrin receptor 1 (TfR1)-dependent and the surface expression of TfR1 was higher in infected cultures, suggesting a novel arenaviral dissemination strategy in hematopoietic progenitor cells. Although proliferation, survival, and commitment in JUNV-infected cultures were normal, viral infection impaired thrombopoiesis by decreasing in vitro proplatelet formation, platelet release, and P-selectin externalization via a bystander effect. The decrease in platelet release was also TfR1-dependent, mimicked by poly(I:C), and type I interferon (IFN α/β) was implicated as a key paracrine mediator. Among the relevant molecules studied, only the transcription factor NF-E2 showed a moderate decrease in expression in megakaryocytes from either infected cultures or after type I IFN treatment. Moreover, type I IFN-treated megakaryocytes presented ultrastructural abnormalities resembling the reported thrombocytopenic NF-E2−/− mouse phenotype. Our study introduces a potential mechanism for thrombocytopenia in VHF and other diseases associated with increased bone marrow type I IFN levels.

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“…That so many of these compounds both induce and inhibit apoptosis, by similar mechanisms in different cell types, is surprising. In megakaryocytes, for example, prostacyclin induced cAMP antagonises apoptosis promoted by NO (Pozner et al 2005), yet prostacyclin induced cAMP in VSMC cells initiates apoptosis (Li et al 2004). Arsenic trioxide also promotes cAMP generation (Abudoureyimu and Muhemaitibake 2017) although, unlike the adenyl cyclase stimulating properties of epinephrine, forskolin and prostacyclin, the mechanism is obscure.…”

Section: Modulators Of Apoptosismentioning

confidence: 99%

Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

Williams

2020

gpb

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Chemical instigators and modulators of tumourigenesis influence cell signal transduction pathways. Cyclic nucleotides and steroid hormones may contribute to the process of carcinogenesis or provide protection via apoptotic mechanisms. Although several pharmacologic classes of compounds influence cyclic nucleotide levels markedly, less is known about the class effects of promoters and blockers of tumourigenesis and apoptosis. This molecular modeling study uses cyclic nucleotide templates to investigate relative molecular similarity within compounds modulating tumourigenesis and apoptosis. Findings, in respect of superimposition and molecular fit of the investigated compounds, are related to their individual effects on cyclic nucleotide pharmacology. Modulators of tumourigenesis and estrogen receptor sub-type ligands relate to cyclic nucleotide structure. Estradiol and GPER ligands provide a similar pattern of fit to adenine nucleotide. Chemically diverse modulators of apoptosis, including K + channel ligands, fit to different components of cyclic nucleotide structure. Compounds modulating Ca 2+ entry and IP3 receptors relate structurally to the nucleotide dioxaphosphinin moiety. Relative molecular similarity within the structures of apoptosis and tumourigenesis modulators identifies a unifying property within chemically disparate compounds. The ubiquitous generation of oxidative stress and ROS in cells by apoptosis modulating compounds may relate to the disruption of cyclic nucleotide regulated homeostasis mechanisms.

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Prostacyclin prevents nitric oxide‐induced megakaryocyte apoptosis

Cited by 18 publications

References 43 publications

Differential roles of cAMP and cGMP in megakaryocyte maturation and platelet biogenesis

Differential roles of cAMP and cGMP in megakaryocyte maturation and platelet biogenesis

Junín Virus Infection of Human Hematopoietic Progenitors Impairs In Vitro Proplatelet Formation and Platelet Release via a Bystander Effect Involving Type I IFN Signaling

Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

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