Legumain Promotes Atherosclerotic Vascular Remodeling

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.

<p>Associations of Interleukin 10, Matrix Metallopeptidase 9, and Legumain with Blood Pressure Variability and Neurologic Outcomes in Patients with Ischemic Stroke</p>

“…This again suggested BPV triggered vascular inflammation could be a reason for poor prognosis in ischemic stroke, since the three biomarkers we investigated were also reported to be involved in the regulation of vascular inflammation in hypertension and atherosclerosis. 22,[26][27][28] Some limitations should be noticed in our study. First, the study included a small sample size, which might result in a limited statistical power.…”

“…This again suggested BPV triggered vascular inflammation could be a reason for poor prognosis in ischemic stroke, since the three biomarkers we investigated were also reported to be involved in the regulation of vascular inflammation in hypertension and atherosclerosis. 22 , 26–28 …”

“…21 Legumain was found to promote atherosclerotic vascular remodeling by enhancing the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. 22 The abnormal expression patterns of these factors might be related to abnormal BPV in ischemic stroke but yet to prove. The study aimed to investigate the associations of IL-10, MMP-9, and legumain with BPV and neurologic outcome of patients with ischemic stroke.…”

Serum Legumain Is Associated with Peripheral Artery Disease in Patients with Type 2 Diabetes

“…Legumain gene expression could be regulated by proinflammatory cytokines such as interleukin-1 β (IL-1 β ), interferon- γ (IFN- γ ), or tumor necrosis factor- α (TNF- α ) [ 28 ]. Legumain promoted atherosclerotic vascular remodeling by enhancing macrophage foam cell formation; VSMC migration; and collagen-3, fibronectin, and elastin production by VSMCs [ 29 ]. Papaspyridonos et al demonstrated that legumain was coexpressed with matrix metalloproteinases (MMPs), so it was regarded as a contributor to plaque rupture [ 30 ].…”

Legumain in cardiovascular disease: Culprit or ally?

“…Stimulation of M1 macrophages with cholesterol crystals results in legumain release [13]. Furthermore, in ApoE −/− mice, legumain infusion enhances atherosclerosis, presumably by promoting extracellular matrix degradation and monocyte and VSMC migration [15]. Together, this evidence points to a contributory role of legumain in plaque destabilization and rupture.…”