Abstract
Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe−/− mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe−/− mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe−/− mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.
Highlights
Atherosclerosis is characterized by a complex process of vascular injury; inflammation, with monocyte adhesion to endothelial cells (ECs); lipid deposition within macrophage foam cells; neointimal hyperplasia, involving vascular smooth muscle cells (VSMCs); and extracellular matrix (ECM) remodeling [1,2]
Macrophage foam cell formation is characterized by cholesterol ester accumulation, which depends on the balance between the uptake of oxidized low-density lipoprotein through scavenger receptor class A (SR-A) or CD36 and the efflux of free cholesterol, controlled by ATP-binding cassette transporter A1 (ABCA1) [6,7]
It is worth noting that legumain did promote atherosclerotic vascular remodeling, associated with increased ECM production via the PI3K/Akt pathway, in VSMCs
Summary
Atherosclerosis is characterized by a complex process of vascular injury; inflammation, with monocyte adhesion to endothelial cells (ECs); lipid deposition within macrophage foam cells; neointimal hyperplasia, involving vascular smooth muscle cells (VSMCs); and extracellular matrix (ECM) remodeling [1,2]. Legumain plays a role in the processing of antigens for MHC class II presentation in the lysosomes of antigen presenting cells [14] and it supports human Th1 cell induction [15]. The expression and secretion of legumain increase during differentiation from monocytes to macrophages [17,21]. Legumain increases the migration of human monocytes [26], but inhibits the oxLDL-induced apoptosis of human macrophages [25]. Legumain increases the migration and proliferation of human umbilical vein endothelial cells (HUVECs) [26]. The specific role of legumain in the pathophysiology of atherosclerosis has not yet been determined
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