Open Access Dissertation
Date of Award
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 Cnn2 gene, 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 the same level of acetylated low-density lipoprotein (LDL) as that of wild type (WT) macrophages but the resulting foam cells had significantly less impaired 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.
Liu, Rong, "Calponin And Cytoskeleton Dynamics In Macrophage Functions And The Pathogenesis Of Atherosclerosis" (2016). Wayne State University Dissertations. 1650.