Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8536781 | Pharmacology & Therapeutics | 2018 | 36 Pages |
Abstract
Atherosclerosis is a dynamic and progressive inflammatory process in the intimal layer of large and medium-sized arteries, and it is the major contributor to the atherosclerotic cardiovascular disease (ACVD), the leading cause of death worldwide. In an atherosclerotic plaque, phagocytosis of apoptotic cells occurs through an intricate process designated efferocytosis. Defective efferocytosis has emerged as a causal factor in the etiopathogenesis of atherosclerosis and its progression into overt ACVD. Both specialized phagocytes (macrophages and dendritic cells) and non-specialized cells with phagocytic capabilities (smooth muscle and endothelial cells) are involved in the efferocytotic process. Moreover, several signaling and regulatory molecules are involved in the different steps of efferocytosis, and they include “Find-Me” signals (lysophosphatidylcholine), “Eat-Me” signals [phosphatidylserine, Mer tyrosine kinase (MerTK), and milk fat globule-EGF factor 8], and “Don't Eat-Me” signals [cluster of differentiation 47 (CD47)]. Regulation of efferocytosis is in a close nexus with inflammation, the key component in atherosclerosis. The predominance of pro-inflammatory and anti-inflammatory molecules plays a crucial role in lesion progression and regression, respectively. Polarization of macrophages towards the M1 phenotype causes them to secrete proinflammatory cytokines, while polarization towards the M2 phenotype causes them to secrete of anti-inflammatory cytokines, including interleukin-10 and transforming growth factor β, so tending to shift the balance towards resolution of the inflammation. Dysfunction of any regulatory signal may cause expansion of the necrotic core of an atherosclerotic plaque with ensuing conversion of the plaque into an unstable plaque with an increased susceptibility to rupture and to atherothrombotic complication. In this review we aim at elucidating the determinant factors and pathways of efferocytosis which can be considered as potential novel targets when striving to develop more personalized and efficient treatment regimens for patients with ACVD.
Keywords
ABCSirt1NF-κBPI3KAICARLPSERK5ABSHDLACSDAMPqRT-PCRMCP-1ABCA1PPARSPMLPCSRFIL-10HSPsDCsTLRS1PARG1HMGB15-LOXUCP2CD14TRAF6RAGELRP1CHDEfferocytosismtROSRSVapoA1TG2TRPMannexin A5ANXA5MFG-E8SMCsSR-BIPTX3IL-12LXRArg2sirtuin1VSMCsoxLDLPtdSerABCG1G-protein–coupled receptorLOX-1ACVDTSP-1SIRPαTRPCIRF5THBSCDKN2BABCA7SMERG2AGvHDIgMTGF-βextracellular-signal-regulated kinase 5brain-specific angiogenesis inhibitor 1cyclin-dependent kinase inhibitor 2BATP binding cassette transporter G1Mer tyrosine kinase5-LipoxygenaseCa2+MϕNOxarginase 1arginase 2antibodiesMyocardial infarctionApoeApolipoprotein A1apolipoprotein ESphingosine-1-phosphateinflammationdamage-associated molecular patternsNADPH oxidaseimmunoglobulin Minterleukin-12Interleukin-10coronary heart diseasecardiovascular diseaseAtherosclerotic cardiovascular diseaseGraft-versus-host diseasetransforming growth factor-betaTransglutaminase 2ThrombospondinThrombospondin-1tumor necrosis factor-alphaToll-like receptorcluster of differentiationcluster of differentiation 14CVDResveratrolquantitative reverse transcription-PCRMERTKDendritic cellsVascular smooth muscle cellsSmooth muscle cellsApoptotic cellsSOCinterferon regulatory factor 5TNF-αnuclear factor kappa Bserum response factorPhosphatidylserinephosphoinositide 3-kinasePhytoalexinTREMLysophosphatidylcholinehigh density lipoproteinOxidized low-density lipoproteinlipopolysaccharideMacrophageMHCmajor histocompatibility complexMyocardinNitric oxidetransient receptor potential canonicalmonocyte chemotactic protein 1Signal regulatory protein αHigh-mobility group box 1 proteinC-reactive proteinCRPHeat shock proteinsAtherosclerotic plaquepentraxin 3calrStore-operated channelliver X receptorcalreticulinCalciumATP-binding cassettemitochondrial reactive oxygen speciestriggering receptor expressed on myeloid cellsReceptor for advanced glycation end productsperoxisome proliferator-activated receptorLectin-like oxidized low-density lipoprotein receptor-1Mannose receptorscavenger receptor class B type I
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Authors
Amir Tajbakhsh, Mehdi Rezaee, Petri T. Kovanen, Amirhossein Sahebkar,