Atherosclerosis xxx (2017) 1e2
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Editorial
sLR11 as a novel predictor of vascular calcification
Keywords: Soluble LR11 Aortic root calcification Familial hypercholesterolemia Vascular calcification Vascular smooth muscle cells
LR11 is a relatively new member of the LDL-receptor family that has been shown to regulate migration of vascular smooth muscle cells (SMCs) in atherogenesis [1]. Vascular calcification predicts cardiovascular morbidity and mortality, and SMCs play pivotal roles. In this issue of Atherosclerosis, Vongpromek et al. reported that circulating soluble form of LR11 (sLR11) levels were associated with aortic root calcification in asymptomatic treated patients with familial hypercholesterolemia [2]. (Fig. 1) LR11 was discovered by the group with Bujo H. co-author of this paper, and designated as LDLR relative with 11 ligand-binding repeats [3]. Investigation about LDL-receptor family members revealed their key roles in the catabolism of many membraneassociated proteins, such as complexes between proteinases and their receptors in addition to lipoprotein metabolism [1]. Recently, key roles of LR11 and sLR11 in atherosclerosis have been elucidated. SMCs migrates from media to intima during the atherosclerotic process, and LR11 is strongly expressed inside the atherosclerotic plaque, especially in SMCs (Fig. 1). Clarified mechanisms of SMCs migration with LR11 are through regulation of the urokinase-type plasminogen activator (uPA) receptor and the platelet derived growth factor (PDGF) receptor [1]. PDGF enhances LR11 expression, and LR11 binds to the uPA receptor on the cell surface or on neighboring cells, inhibiting internalization, and enhancing uPA expression, which results in an increased degradation of the ECM and promotion of SMCs motility. Importantly, LR11 is shed from cell surface as sLR11 and has been shown to be a quite active molecule regulating metabolic morbidities. Ohwaki et al. reported that sLR11 secreted from intimal SMCs accelerates formation of lipid-laden macrophages [4]. Increased sLR11 levels have been reported to correlate with intima-media thickness of carotid arteries in type 2 diabetes [5] of familial hypercholesterolemia [6], coronary organic stenosis, or [7] acute coronary syndrome [8]. Circulating sLR11 is not only a useful marker of atherosclerosis, but has more pathogenic roles. LR11 also binds to lipoprotein lipase (LPL) and degrades it. LPL activity is required for triglyceride-rich lipoprotein (TGRL) uptake into brown adipose tissue (BAT). sLR11 is shown to down-
regulate thermogenesis of BAT, and sLR11 levels in humans show a positive correlation with body mass index and adiposity [9]. It has been reported that TGRL increases LR11 mRNA and sLR11 release [6], LR11 seems to exacerbate atherogenic morbidities associated with hypertriglyceridemia. Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by increased plasma LDL, premature coronary artery disease, and tendon or skin xanthomas. Coronary atherosclerosis is strongly enhanced with life-long increased LDLC levels since birth. Nohara et al. reported that sLR11 was positively correlated with IDL as TGRL, apoE, and HbA1c, in patients with FH [10]. Interestingly, sLR11 was associated with Achilles tendon thickness evaluated by X-ray. Achilles tendon thickening in FH represents tendon xanthomas, cholesterol accumulation in foam cell formation. In this paper, Vongpromek et al. reported that sLR11 was associated with aortic root calcification (ARC) but, intriguingly, not with aortic valve (AVC) or coronary artery calcification (CAC) in asymptomatic patients with FH. sLR11 was correlated with TGRL in male and female patients with FH also in this study. It is not surprising that AVC are different from ARC because the constituting cell types of the aortic valve are quite different from those of the aortic root, but differences between ARC and CAC are less clear. Statin is one of the main drugs treating cardiovascular disease. Statins inhibit the migration of intimal SMCs by decreasing uPA receptor expression via downregulation of the LR11 gene expression. It is complex that vascular calcification is related to both stable and unstable plaque. Usually dense calcification of coronary artery is a marker of stable plaque, and spotty calcification is a marker of unstable plaque. Puri et al. reported statins promote coronary atheroma calcification [11], and Zhao et al. reported statins showed no effect on aortic valve function and calcification [12]. The impact of statins may be different on the aortic root, and CAC data on longterm treatment with statins may not reflect recent morbidity affecting LR11, but further investigation would be required. Recent findings in the atherogenic process have shown that medial SMCs migrated from media into intima, and SMC phenotype switching occurs. SMCs change into macrophage-like cells and presumably into more than half of the total foam cells in human coronary plaque. Local SMCs switch phenotype into calcifying vascular cells with TGRL in plaque. Foam cells derived from SMCs are reported to lose cholesterol efflux capacity with ABCA1 [13]. It is an attractive hypothesis that LR11 could be the key molecule switching in these atherogenic processes, by regulating the migration and proliferation of vascular SMCs. Recent reports suggest that LR11 might be a novel target for the residual risk of cardiovascular disease.
http://dx.doi.org/10.1016/j.atherosclerosis.2017.07.025 0021-9150/© 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Nohara, sLR11 as a novel predictor of vascular calcification, Atherosclerosis (2017), http://dx.doi.org/ 10.1016/j.atherosclerosis.2017.07.025
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Editorial / Atherosclerosis xxx (2017) 1e2
Fig. 1. LR11 regulates SMCs migration and proliferation.
Conflict of interest The author declared he does not have anything to disclose regarding conflict of interest with respect to this manuscript. Financial support The author wishes to acknowledge the support by JSPS KAKENHI Grant Number 17K09859. References [1] H. Bujo, Y. Saito, Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family, Arterioscler. Thromb. Vasc. Biol. 26 (2006) 1246e1252. [2] R. Vongpromek, S. Bos, G.R. Ten Kate, H. Bujo, M. Jiang, K. Nieman, W. Schneider, J.E. Roeters van Lennep, A.J.M. Verhoeven, E.J.G. Sijbrands, M.T. Mulder, Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia, Atherosclerosis (2017 Jun 9), http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.018 pii: S0021-9150(17)30268-X, [Epub ahead of print]. [3] H. Yamazaki, H. Bujo, J. Kusunoki, K. Seimiya, T. Kanaki, N. Morisaki, W.J. Schneider, Y. Saito, Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member, J. Biol. Chem. 271 (1996) 24761e24768.
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Atsushi Nohara Cholesterol Clinic, Department of Cardiology, Kanazawa University Hospital, Kanazawa University Health Service Center, Takara-machi 13-1, Kanazawa 920-8641, Japan E-mail address:
[email protected]. 20 July 2017 Available online xxx
Please cite this article in press as: A. Nohara, sLR11 as a novel predictor of vascular calcification, Atherosclerosis (2017), http://dx.doi.org/ 10.1016/j.atherosclerosis.2017.07.025