Overexpression Of Chitotriosidase-1 Modulates Macrophage Function And Alters Plaque Morphology In Hyperlipidemic Mice
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2019
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University of Hawaii at Manoa
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Cardiovascular diseases (CVD) are the leading cause of mortality in the world. Responsible for nearly 1/3 of all deaths globally, CVD poses extreme public health challenges and a growing economic burden. Atherosclerosis is fundamental to CVD, and is characterized by the accumulation of plaque within arterial blood vessels. Atherosclerotic plaques are the result of lipid deposition in the subendothelial space, which initiates monocyte infiltration and formation of lipid-laden foam cells derived from macrophages. The inflammatory cascade that follows, promotes plaque formation and development. Disease progression ultimately leads to a number of atherosclerotic pathologies including myocardial infarction and ischemic stroke. Clearly, our greatest efforts are required in exploring novel therapeutic perspectives that ameliorate inflammation and prevent dysfunctional cholesterol metabolism. My work has been directed at investigating the potential role of macrophage chitotriosidase-1 (CHIT1) overexpression in dampening production of pro-inflammatory cytokines and inhibiting macrophage foam cell formation. We generated an atherosclerotic mouse model constitutively overexpressing CHIT1 by crossing hyperlipidemic Ldl-r-/- mice with transgenic, CHIT1 overexpressing mice. We carried out in vitro experiments aimed at elucidating the effect of CHIT1 overexpression on macrophage inflammatory mechanisms, cholesterol metabolism, and invasion. In vitro, macrophage overexpression resulted in diminished mRNA transcription of important pro-inflammatory mediators and increased expression of cytokines involved in immune cell migration and anti-inflammatory processes. We also observed that CHIT1 overexpression in BMDM enhanced macrophage invasiveness. The CHIT1-overexpressing, atherosclerotic mouse model (Ldlr-/--CHIT1-OE) facilitated a long-term in vivo mouse study. Animals in the study were fed a high-fat diet for 12 weeks which resulted in robust atherosclerotic progression. Although CHIT1 overexpression in Ldlr-/- mice did not affect plaque development when compared to control mice, we were able to observe significant differences in plaque morphology related to the deposition of ECM components. This unexpected finding may suggest that CHIT1 overexpression affects plaque stability in atherosclerotic mice. The possibility of CHIT1 mediated athero-protection may in fact lie in its ability to augment ECM composition in atherosclerotic plaques.
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Atherosclerosis--Molecular aspects, Macrophages, Atherosclerotic plaque
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