Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

Kumari, Sharda; Chaurasia, Susheel N.; Nayak, Manasa K.; Mallick, Ram L.; Dash, Debabrata

doi:10.1074/jbc.m114.615948

Cited by 45 publications

(29 citation statements)

References 38 publications

(52 reference statements)

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“…5G and H). Furthermore, to clarify the role played by Sirt1 expression, we evaluated the effects of EX-527, a Sirt1 inhibitor, on the effect of XN on platelet activation and ROS accumulation [46]. In the presence of EX-527 + XN, we saw much lower levels of inhibition of ROS accumulation and platelet aggregation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Xin

Wei

et al. 2017

Free Radical Biology and Medicine

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Aim As the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism. Approach and Results Using ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner. Conclusions XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.

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Section: Resultsmentioning

confidence: 99%

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Xin

Wei

et al. 2017

Free Radical Biology and Medicine

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“…Casp3 is one of the executioner caspases and its role in TNF‐α induced apoptosis (receptor‐mediated apoptosis) has been implicated (Aggarwal, ). SIRT1 deacetylates and suppresses the transcription factor NF‐κB (responsible for induction of pro‐apoptotic factors) and promotes cell survival by inhibiting OS‐induced apoptosis (Kemelo et al, ; Kumari et al, ). Multiple mechanisms are therefore involved in GalN‐induced hepatotoxicity that include downregulation of SIRT1 gene expression with subsequent upregulation of the pivotal downstream target NF‐κB, which in turn mediates proinflammatory cytokines release and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…They are also implicated in determining the balance between apoptosis, cell survival, and cell proliferation (Balcerczyk & Pirola, ). A number of studies demonstrated that sirtuin 1 (SIRT1) promotes either cell survival (by inhibiting apoptosis) or stress‐induced cellular senescence (including DNA damage and oxidative stress [OS]), and plays therefore a critical role in the regulation of cell fate and stress response (Kumari, Chaurasia, Nayak, Mallick, & Dash, ). SIRT1 acts on many substrates, including histones, transcription factor nuclear factor‐kappa beta (NF‐κB), FoxO, and p53, and deacetylation of these targets is a mechanism by which cells alter the transcriptional activity of many genes both quantitatively and qualitatively in response to different stress conditions (Kemelo, Wojnarová, Canová, & Farghali, ; Kotas, Gorecki, & Gillum, ).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of sulfated polysaccharide isolated fromUlva fasciataagainst galactosamine-induced liver injury in rats

Said

Ezz

Matloub³

2017

J Food Biochem

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The hepatoprotective potential of sulfated polysaccharide (SPS) from Ulva fasciata seaweed against galactosamine (GalN)‐induced hepatotoxicity was investigated. Subcutaneous injection of 300 mg/kg GalN into rats caused acute liver injury as manifested by the downregulation of sirtuin 1 (SIRT1) gene expression and induction of hepatic proinflammatory cytokines production, and fibrosis as demonstrated by the significant upregulation of hepatic transforming growth factor beta 1 (TGF‐β1) and collagen type I (Col1a1) genes expression. Conversely, pretreatment of rats with SPS attenuated GalN‐induced hepatotoxicity via inducing liver SIRT1 gene expression and suppressing proinflammatory cytokines synthesis, which ultimately reduced liver fibrogenesis. Histological findings of liver tissues verified the biochemical data. The study clarified some of the molecular mechanisms by which SPS isolated from U. fasciata protects the liver against acute GalN‐induced injury. Practical applications The results suggest the potential use of this edible SPS isolated from Ulva fasciata as a food additive to prevent and/or attenuate development of hepatitis.

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“…Since flow cytometry data suggest the possibility of apoptosis induced by the PF4-containing complexes, we used Western blot analysis to test this assumption by quantifying apoptotic molecular markers. We quantified the expression of Bax and Bcl-X L , the components of the Bcl-2 gene family that are known to be expressed in platelets [20]. Bcl-X L is an anti-apoptotic protein that modulates apoptosis by controlling mitochondrial membrane permeability and regulating the release of cytochrome c [21].…”

Section: Apoptotic Markers In Platelets Induced By Kko/pf4mentioning

confidence: 99%

Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways

Mordakhanova

Невзорова

Synbulatova

et al. 2020

IJMS

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Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. HIT is caused by antibodies that recognize complexes of platelet factor 4 and heparin. The pathogenic mechanisms of this condition are not fully understood. In this study, we used flow cytometry, fluorimetry, and Western blot analysis to study the direct effects of pathogenic immune complexes containing platelet factor 4 on human platelets isolated by gel-filtration. HIT-like pathogenic immune complexes initially caused pronounced activation of platelets detected by an increased expression of phosphatidylserine and P-selectin. This activation was mediated either directly through the FcγRIIA receptors or indirectly via protease-activated receptor 1 (PAR1) receptors due to thrombin generated on or near the surface of activated platelets. The immune activation was later followed by the biochemical signs of cell death, such as mitochondrial membrane depolarization, up-regulation of Bax, down-regulation of Bcl-X L , and moderate activation of procaspase 3 and increased calpain activity. The results show that platelet activation under the action of HIT-like immune complexes is accompanied by their death through complex apoptotic and calpain-dependent non-apoptotic pathways that may underlie the low platelet count in HIT.Despite a lot of information being available on triggering factors and pathogenic mechanisms involved in HIT, the causes of thrombocytopenia in HIT are not well delineated. One possibility is that a low platelet count is triggered by the clearance of Ab-coated platelets in the spleen and potentially the liver. The second possibility is that platelets are consumed within thrombi; however, it is unclear if sufficient platelets are incorporated into thrombi to cause thrombocytopenia. The third potential explanation involves platelet disintegration via microvesiculation [6,7], but whether this mechanism is responsible for the low platelet count is unclear. Our recent studies suggest that platelets activated by thrombin undergo fatal dysfunction and cytoplasmic fragmentation clearly distinct from what happens when platelets are activated by adenosine diphosphate (ADP) or collagen [8,9]. Based on these and other findings, we hypothesized that platelets activated in HIT through FcγRIIA undergo activation followed by death, leading to thrombocytopenia with the removal of dead platelets perhaps by neutrophils and macrophages.In this work, we studied the direct effects of PF4-containing HIT-pathogenic immune complexes on isolated human platelets. As a tool, we used two isotype-matched murine anti-human PF4/heparin monoclonal Abs that mimic their human counterparts in vitro [10], and in vivo the pathogenic monoclonal anti-PF4/heparin antibody (KKO) causes HIT in an animal model, while the non-pathogenic monoclonal anti-PF4/heparin antibody (RTO) does not [11]. Importantly, ELISA-positive plasma samples from patients suspected of having HIT contain Abs that show hep...

show abstract

Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

Cited by 45 publications

References 38 publications

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Protective effect of sulfated polysaccharide isolated fromUlva fasciataagainst galactosamine-induced liver injury in rats

Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways

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