Apoptotic Ablation of Platelets Reduces Atherosclerosis in Mice With Diabetes

Lee, Man K.S.; Kraakman, Michael J; Dragoljevic, Dragana; Hanssen, Nordin M.J.; Flynn, Michelle; Al-Sharea, Annas; Sreejit, Gopalkrishna; Veiga, Camilla Bertuzzo; Cooney, Olivia D.; Baig, Fatima; Morriss, Elizabeth; Cooper, Mark E.; Josefsson, Emma C.; Kile, Benjamin T.; Nagareddy, Prabhakara R; Murphy, Andrew

doi:10.1161/atvbaha.120.315369

Cited by 13 publications

(7 citation statements)

References 57 publications

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“…59 Ablation of platelet apoptosis can reduce atherosclerosis in diabetes mice, leading to a more stable plaque by preventing platelet-monocyte interactions and subsequently monocyte activation. 60 The current advances in anti-inflammatory therapies have identified an inflammatory mediator effect of thrombosis secondary to platelet activation. 61 …”

Section: Cells Involved In Atherosclerosismentioning

confidence: 99%

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention

Kong

Cui

Huang

et al. 2022

Sig Transduct Target Ther

329

173

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Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors. Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis. Several signaling pathways, that are associated with the inflammatory response, have been implicated within atherosclerosis such as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt signaling pathways, which are of importance for atherosclerosis development and regression. Targeting inflammatory pathways, especially the NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β, could represent an attractive new route for the treatment of atherosclerotic diseases. Herein, we summarize the knowledge on cellular participants and key inflammatory signaling pathways in atherosclerosis, and discuss the preclinical studies targeting these key pathways for atherosclerosis, the clinical trials that are going to target some of these processes, and the effects of quelling inflammation and atherosclerosis in the clinic.

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Section: Cells Involved In Atherosclerosismentioning

confidence: 99%

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention

Kong

Cui

Huang

et al. 2022

Sig Transduct Target Ther

329

173

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“…The high platelet count is likely due to increased thrombopoiesis, which is induced by higher plasma levels of thrombopoietin and IL-6 [ 69 , 70 , 71 ] or is caused by iron deficiency [ 72 ]. Some studies describe a correlation between high platelet counts and atherosclerosis [ 73 , 74 , 75 ]. In our research, higher values of platelets were registered in patients with ulcerative colitis and atherosclerosis and patients with ulcerative colitis, which coincides with the results of the mentioned studies.…”

Section: Discussionmentioning

confidence: 99%

Atherosclerotic Cardiovascular Disease in Inflammatory Bowel Disease: The Role of Chronic Inflammation and Platelet Aggregation

Lugonja

Pantic²,

Milovanović

et al. 2023

Medicina

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Background and Objectives: Atherosclerosis is one of inflammatory bowel disease’s most significant cardiovascular manifestations. This research aimed to examine the relationship between biochemical, haemostatic, and immune parameters of atherosclerosis and ulcerative colitis patients and its relationship to platelet aggregation. Materials and Methods: A clinical, observational cross-sectional study was performed, during which the tested parameters were compared in the experimental and control groups. The patients were divided into four groups. The first group had 25 patients who had ulcerative colitis and atherosclerosis. The second group included 39 patients with ulcerative colitis without atherosclerosis. The third group comprised 31 patients suffering from atherosclerosis without ulcerative colitis, and the fourth group comprised 25 healthy subjects. Results: In our study, we registered statistically higher levels of inflammatory markers like SE, CRP, Le, fecal calprotectin, TNF-α, and IL-6, as well as the higher value of thrombocytes and thrombocyte aggregation in the group of patients with ulcerative colitis compared to the control group. Lower levels of total cholesterol and LDL were also recorded in patients with ulcerative colitis and atherosclerosis and ulcerative colitis without atherosclerosis compared to healthy control. Triglyceride and remnant cholesterol were higher in patients with ulcerative colitis and atherosclerosis when compared to patients with ulcerative colitis and healthy control but lower than in patients with atherosclerosis only. Conclusions: Several inflammatory markers and platelet aggregation could be good discrimination markers for subjects with ulcerative colitis with the highest risk of atherosclerosis.

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“…Auto-antibodies targeting the GPIIb-IIIa and GPIb-IX platelet receptors induce apoptotic signaling in platelets, contributing to ITP [ 3 , 36 ]. Conversely, the induction of platelet apoptosis may have therapeutic benefits in the treatment of atherosclerosis [ 37 ]. Consequently, an improved understanding of the pro- and anti-apoptotic signaling mechanisms in platelets will aid in advancing improved therapeutic approaches for multiple diseases whose outcomes are influenced by circulating platelet availability.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis in platelets is independent of the actin cytoskeleton

Silva

Paul²,

Kim³

2022

PLoS ONE

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Homeostasis between platelet production and clearance is essential for human health. A critical facet of the balance that facilitates platelet clearance from the circulation is apoptosis (programmed cell death). The precise cellular mechanisms that underpin platelet apoptosis are not defined. In nucleated cells, reorganization of the actin cytoskeleton is known to regulate platelet apoptosis. However, the role of the actin cytoskeleton in regulating apoptosis in platelets has not been extensively studied as they are anucleate and exhibit a distinctive physiology. Here, apoptosis was induced in washed human platelets using ABT-737, a BH3-mimetic drug. Mitochondrial depolarization was measured using the ratiometric dye JC-1; surface phosphatidylserine (PS) exposure was measured by annexin V binding; caspase-3 activation was measured by Western blotting. All three apoptotic markers were unaffected by the presence of either the actin depolymerizing drug cytochalasin D or the actin polymerizing drug jasplakinolide. Moreover, platelets were isolated from wild-type (WT) mice and mice deficient in gelsolin (Gsn), an actin-binding protein that is essential for normal cytoskeletal remodeling. In response to ABT-737, gelsolin-null (Gsn-/-) platelets initially showed accelerated PS exposure relative to WT platelets, however, both WT and Gsn-/- platelets exhibited similar levels of mitochondrial depolarization and caspase-3 activation in response to ABT-737. We conclude that ABT-737 induces established markers of platelet apoptosis in an actin-independent manner.

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Apoptotic Ablation of Platelets Reduces Atherosclerosis in Mice With Diabetes

Cited by 13 publications

References 57 publications

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention

Atherosclerotic Cardiovascular Disease in Inflammatory Bowel Disease: The Role of Chronic Inflammation and Platelet Aggregation

Apoptosis in platelets is independent of the actin cytoskeleton

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