title: Deletion of calponin 2 in macrophages alters cytoskeleton-based functions and attenuates the development of atherosclerosis.
abstract: Arterial atherosclerosis is an inflammatory disease. Macrophages play a major role in the pathogenesis and progression of atherosclerotic lesions. Modulation of macrophage function is a therapeutic target for the treatment of atherosclerosis. Calponin is an actin-filament-associated regulatory protein that inhibits the activity of myosin-ATPase and dynamics of the actin cytoskeleton. Encoded by the gene Cnn2, calponin isoform 2 is expressed at significant levels in macrophages. Deletion of calponin 2 increases macrophage migration and phagocytosis. In the present study, we investigated the effect of deletion of calponin 2 in macrophages on the pathogenesis and development of atherosclerosis. The results showed that macrophages isolated from Cnn2 knockout mice ingested a similar level of acetylated low-density lipoprotein (LDL) to that of wild type (WT) macrophages but the resulting foam cells had significantly less hindered velocity of migration. Systemic or myeloid cell-specific Cnn2 knockouts effectively attenuated the development of arterial atherosclerosis lesions with less macrophage infiltration in apolipoprotein E knockout mice. Consistently, calponin 2-null macrophages produced less pro-inflammatory cytokines than that of WT macrophages, and the up-regulation of pro-inflammatory cytokines in foam cells was also attenuated by the deletion of calponin 2. Calponin 2-null macrophages and foam cells have significantly weakened cell adhesion, indicating a role of cytoskeleton regulation in macrophage functions and inflammatory responses, and a novel therapeutic target for the treatment of arterial atherosclerosis.
authors: Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.
authors: Rong
authors: R
authors: Liu
authors: Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: jjin@med.wayne.edu.
authors: J-P
authors: JP
authors: Jin
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000172:deficiency*; D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D018836:Inflammation Mediators; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency*; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic / Q000473:pathology; D021381:Protein Transport; D000096985:Calponins
chemical_list: D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D000096985:Calponins
keywords: ApoE knockout mouse; Atherosclerosis; Calponin; Cell adhesion; Cell motility; Macrophage