Acute CD47 Blockade During Ischemic Myocardial Reperfusion Enhances Phagocytosis-Associated Cardiac Repair

Zhang, Shuang; Yeap, Xin Yi; DeBerge, Matthew; Naresh, Nivedita K.; Wang, Kevin; Jiang, Zhengxin; Wilcox, Jane E.; White, Steven M.; Morrow, John; Burridge, Paul W.; Procissi, Daniele; Scott, Evan A.; Frazier, William A.; Thorp, Edward B.

doi:10.1016/j.jacbts.2017.03.013

Cited by 44 publications

(49 citation statements)

References 46 publications

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“…In effective efferocytosis, the engulfment of ACs and NCs by "Eat-Me" signals occurs together with downregulation of "Don't-Eat-Me" signals such as CD47 and CD31 [45]. There is a growing body of literature that recognises the importance of CD47 in chronic disease [46,47]. Based on previously published papers, CD47 signaling regulates multiple distinct cellular processes such as efferocytosis, Ca 2+ homeostasis, and nitric oxide (NO) [47,48].…”

Section: The Role Of Ca 2+ In "Don't Eat Me" Signallingmentioning

confidence: 99%

“…There is a growing body of literature that recognises the importance of CD47 in chronic disease [46,47]. Based on previously published papers, CD47 signaling regulates multiple distinct cellular processes such as efferocytosis, Ca 2+ homeostasis, and nitric oxide (NO) [47,48]. CD47 regulates the Ca 2+ influx into endothelial cells that is integrin dependent.…”

Section: The Role Of Ca 2+ In "Don't Eat Me" Signallingmentioning

confidence: 99%

“…Enhanced CD47 also leads to defective phagocytic clearance via macrophages on the surface of dying cardiomyocytes in vitro. Following myocardial ischemia and reperfusion, inhibition of integrin-associated protein CD47 with blocking antibodies increased the clearance of dead myocytes by cardiac phagocytes and increased the resolution of cardiac inflammation [47].…”

Section: The Role Of Ca 2+ In "Don't Eat Me" Signallingmentioning

confidence: 99%

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Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

Tajbakhsh

Kovanen

Rezaee

et al. 2019

JCM

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In atherosclerosis, macrophages in the arterial wall ingest plasma lipoprotein-derived lipids and become lipid-filled foam cells with a limited lifespan. Thus, efficient removal of apoptotic foam cells by efferocytic macrophages is vital to preventing the dying foam cells from forming a large necrotic lipid core, which, otherwise, would render the atherosclerotic plaque vulnerable to rupture and would cause clinical complications. Ca 2+ plays a role in macrophage migration, survival, and foam cell generation. Importantly, in efferocytic macrophages, Ca 2+ induces actin polymerization, thereby promoting the formation of a phagocytic cup necessary for efferocytosis. Moreover, in the efferocytic macrophages, Ca 2+ enhances the secretion of anti-inflammatory cytokines. Various Ca 2+ antagonists have been seminal for the demonstration of the role of Ca 2+ in the multiple steps of efferocytosis by macrophages. Moreover, in vitro and in vivo experiments and clinical investigations have revealed the capability of Ca 2+ antagonists in attenuating the development of atherosclerotic plaques by interfering with the deposition of lipids in macrophages and by reducing plaque calcification. However, the regulation of cellular Ca 2+ fluxes in the processes of efferocytic clearance of apoptotic foam cells and in the extracellular calcification in atherosclerosis remains unknown. Here, we attempted to unravel the molecular links between Ca 2+ and efferocytosis in atherosclerosis and to evaluate cellular Ca 2+ fluxes as potential treatment targets in atherosclerotic cardiovascular diseases.

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Section: The Role Of Ca 2+ In "Don't Eat Me" Signallingmentioning

confidence: 99%

Section: The Role Of Ca 2+ In "Don't Eat Me" Signallingmentioning

confidence: 99%

Section: The Role Of Ca 2+ In "Don't Eat Me" Signallingmentioning

confidence: 99%

See 1 more Smart Citation

Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

Tajbakhsh

Kovanen

Rezaee

et al. 2019

JCM

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“…Primarily, CAP led to over activation of CD47 in spleen and heart post MI. Apoptotic myocytes that expressed CD47 interacted with the signal regulatory protein (SIRP‐α) to activate “don't eat me” signal while splenic leukocytes play an important role in clearance of post‐MI inflammation in the infarcted LV . Thus, elevated CD47 expression in neutrophils triggered a resistance to neutrophil clearance post MI.…”

Section: Discussionmentioning

confidence: 99%

Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury

Halade

Kain

Wright

et al. 2018

Journal of Leukocyte Biology

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Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated "don't eat me" signal (CD47) with reduced total Mϕs (F4/80 ) and reparative Mϕs (F4/80/Ly6C /CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G ) were intensified and reduced reparative neutrophils (Ly6G /CD206 ) and Mϕs (F4/80/Ly6C ) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non-resolving inflammation.

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“…Recently, CD47-blocking antibodies have been effective at restoring defective atherosclerotic phagocytosis ( 97 , 98 ) and preventing atherosclerosis in experimental mouse models ( 99 ). More recent studies ( 100 ), suggest that early targeting of CD47 in the myocardium after infarction may be a new viable strategy, in combination with current standards of care, to enhance the efficacy of wound repair in the ischemic heart, and specifically through promotion of enhanced cardiomyocyte phagocytosis. However, the titration of anti-CD47 antibodies will likely need to be optimized to prevent phagoptosis of live cells ( 101 ).…”

Section: Phagocytic Receptor Targets and Stimuli In Heartmentioning

confidence: 99%

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

et al. 2017

Self Cite

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Phagocytic sensing and engulfment of dying cells and extracellular bodies initiate an intracellular signaling cascade within the phagocyte that can polarize cellular function and promote communication with neighboring non-phagocytes. Accumulating evidence links phagocytic signaling in the heart to cardiac development, adult myocardial homeostasis, and the resolution of cardiac inflammation of infectious, ischemic, and aging-associated etiology. Phagocytic clearance in the heart may be carried out by professional phagocytes, such as macrophages, and non-professional cells, including myofibrolasts and potentially epithelial cells. During cardiac development, phagocytosis initiates growth cues for early cardiac morphogenesis. In diseases of aging, including myocardial infarction, heightened levels of cell death require efficient phagocytic debridement to salvage further loss of terminally differentiated adult cardiomyocytes. Additional risk factors, including insulin resistance and other systemic risk factors, contribute to inefficient phagocytosis, altered phagocytic signaling, and delayed cardiac inflammation resolution. Under such conditions, inflammatory presentation of myocardial antigen may lead to autoimmunity and even possible rejection of transplanted heart allografts. Increased understanding of these basic mechanisms offers therapeutic opportunities.

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Acute CD47 Blockade During Ischemic Myocardial Reperfusion Enhances Phagocytosis-Associated Cardiac Repair

Cited by 44 publications

References 46 publications

Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

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