Calpain Activator Dibucaine Induces Platelet Apoptosis

Zhang, Weilin; Li, Jun; Sun, Ruichen; Zhao, Lili; Du, Juan; Ruan, Changgeng; Dai, Kesheng

doi:10.3390/ijms12042125

Cited by 28 publications

(17 citation statements)

References 31 publications

(50 reference statements)

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“…Induction of calpain activity in platelets has also been linked to other markers of platelet apoptosis. 45 Like HlyA, bacterial-derived ␣-toxin forms pores in target cells and elicits hemolysis. 46 ␣-toxin also activates platelets and triggers cytoskeletal reorganization.…”

Section: Discussionmentioning

confidence: 99%

Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets

Kraemer

Campbell

Schwertz

et al. 2012

Blood

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Bacteria can enter the bloodstream in response to infectious insults. Bacteremia elicits several immune and clinical complications, including thrombocytopenia. A primary cause of thrombocytopenia is shortened survival of platelets. We demonstrate that pathogenic bacteria induce apoptotic events in platelets that include calpain-mediated degradation of Bcl-x L , an essential regulator of platelet survival. Specifically, bloodstream bacterial isolates from patients with sepsis induce lateral condensation of actin, impair mitochondrial membrane potential, and degrade Bcl-x L protein in platelets. Bcl-x L protein degradation is enhanced when platelets are exposed to pathogenic Escherichia coli that produce the poreforming toxin ␣-hemolysin, a response that is markedly attenuated when the gene is deleted from E coli. We also found that nonpathogenic E coli gain degrading activity when they are forced to express ␣-hemolysin. Like ␣-hemolysin, purified ␣-toxin readily degrades Bcl-x L protein in platelets, as do clinical Staphylococcus aureus isolates that produce ␣-toxin. Inhibition of calpain activity, but not the proteasome, rescues Bcl-x L protein degradation in platelets coincubated with pathogenic E coli including ␣-hemolysin producing strains. This is the first evidence that pathogenic bacteria can trigger activation of the platelet intrinsic apoptosis program and our results suggest a new mechanism by which bacterial pathogens might cause thrombocytopenia in patients with bloodstream infections. IntroductionBacteremia is a leading cause of morbidity and mortality in the United States and worldwide. 1,2 Risk factors for bacteremia include indwelling catheters, 3 trauma, 4 and surgery. 5 Bloodstream infections also are found frequently in patients with malignancies, 6 endocarditis, 7 and urinary tract infections. 8 In severe cases, bacteremia elicits a vigorous immune response that results in sepsis and septic shock. 9 Bloodstream infections often are accompanied by thrombocytopenia. 10 Adverse clinical outcomes commonly are observed in thrombocytopenic patients with documented bacteremia, and the severity of thrombocytopenia is associated with an increase in the rate of mortality of patients in the intensive care unit. 10,11 It generally is presumed that the infectious milieu induces thrombocytopenia by activating platelets that subsequently deposit in microvascular thrombi or get cleared from the circulation. 12 Indeed, bacteria or bacterial products can induce platelet activation by directly or indirectly binding to surface receptors such as integrin ␣ IIb ␤ 3 , GPIb, and TLRs. 13 However, the precise mechanisms that underpin bacteremia-induced thrombocytopenia remain poorly defined.In addition to the biochemical pathways that regulate classic platelet functional responses such as aggregation and adhesion, it has been demonstrated recently that megakaryocytes and platelets possess an intrinsic apoptosis program. 14,15 Key components of the platelet apoptotic pathway include the prosurvival protein Bcl-x L and...

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Section: Discussionmentioning

confidence: 99%

Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets

Kraemer

Campbell

Schwertz

et al. 2012

Blood

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“…Thus, it is conceivable that plasma membrane lipid scrambling will impact the stability of caveolae. To test this hypothesis, we made use of dibucaine, an analgesic, to scramble the lipids across the PM (46,47). To validate the effects of dibucaine, we added Alexa-555-conjugated annexin V, which detects exofacial PtdSer (Fig.…”

Section: Membrane Lipid Scrambling Alters Cav1-gfp Featuresmentioning

confidence: 99%

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane

Hirama

Das

Yang

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerCaveolae are bulb-shaped nanodomains of the plasma membrane that are enriched in cholesterol and sphingolipids. They have many physiological functions, including endocytic transport, mechanosensing, and regulation of membrane and lipid transport. Caveola formation relies on integral membrane proteins termed caveolins (Cavs) and the cavin family of peripheral proteins. Both protein families bind anionic phospholipids, but the precise roles of these lipids are unknown. Here, we studied the effects of phosphatidylserine (PtdSer), phosphatidylinositol 4-phosphate (PtdIns4P), and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) on caveolar formation and dynamics. Using live-cell, single-particle tracking of GFP-labeled Cav1 and ultrastructural analyses, we compared the effect of PtdSer disruption or phosphoinositide depletion with caveola disassembly caused by cavin1 loss. We found that PtdSer plays a crucial role in both caveola formation and stability. Sequestration or depletion of PtdSer decreased the number of detectable Cav1-GFP puncta and the number of caveolae visualized by electron microscopy. Under PtdSer-limiting conditions, the co-localization of Cav1 and cavin1 was diminished, and cavin1 degradation was increased. Using rapamycin-recruitable phosphatases, we also found that the acute depletion of PtdIns4P and PtdIns (4,5)P 2 has minimal impact on caveola assembly but results in decreased lateral confinement. Finally, we show in a model of phospholipid scrambling, a feature of apoptotic cells, that caveola stability is acutely affected by the scrambling. We conclude that the predominant plasmalemmal anionic lipid PtdSer is essential for proper Cav clustering, caveola formation, and caveola dynamics and that membrane scrambling can perturb caveolar stability.

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“…At present, various commonly used biologicals such as, melatonin, vancomycin, balhimycin, cisplatin, arsenic trioxide, aspirin, resveratrol, sesamol, dibucaine, andrographolide, gossypol and carmustine are reported to elicit platelet apoptosis (Table 1) [6,7,11,12,[48][49][50][51][52].…”

Section: Effect Of Pro-apoptotic Biologicals On Plateletsmentioning

confidence: 98%

Biologicals, platelet apoptosis and human diseases: An outlook

Thushara

Hemshekhar

Basappa

et al. 2015

Critical Reviews in Oncology/Hematology

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Platelets, once considered mediators of hemostasis and thrombosis, are now known to be involved in wound healing, inflammation, cardiovascular diseases, diabetes, arthritis, and cancer. Recent reports attest that platelets possess the cellular machinery to undergo apoptosis and that platelet apoptosis can be triggered by myriad stimuli including chemical and physical agonists, and pathophysiological conditions. Augmented rate of platelet apoptosis leads to thrombocytopenia, bleeding disorders and microparticle generation. Despite knowing the significant role of platelets in health and disease, and that any alterations in platelet functions can wreak havoc to the health, the offshoot reactions of therapeutic drugs on platelets and the far-reaching consequences are often neglected. The present review focuses on the impact of platelet apoptosis and the role of platelet-derived microparticles on different pathophysiological conditions. It also touches upon the effects of biologicals on platelets, and discusses the need to overcome the adverse effects of pro-apoptotic drugs through auxiliary therapy.

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Calpain Activator Dibucaine Induces Platelet Apoptosis

Cited by 28 publications

References 31 publications

Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets

Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane

Biologicals, platelet apoptosis and human diseases: An outlook

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