The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low-density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE−/− mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment.

BackgroundIntracranial atherosclerotic stenosis (ICAS) is an important cause of ischemic stroke worldwide. The role of high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C) in the development of ICAS remains to be elucidated. In the current study, we investigated the relationship of HDL-C level and the risk of developing ICAS in Chinese patients with acute ischemic stroke.MethodsFrom October 2007 to June 2009, a total of 1,984 consecutive ischemic stroke patients were evaluated for the presence of symptomatic ICAS by magnetic resonance angiography (MRA). Patients were classified into two groups: intracranial steno-occlusion (ICAS group, n = 888) and non-intracranial stenosis (NICAS group, n = 1096). Serum lipid profiles were analyzed and compared between the ICAS and NICAS group.ResultsSignificantly more patients in ICAS group had low HDL-C level (51.6%) than in the NICAS group (42.9%, P<0.001). The observed association remained significant after adjustment for conventional risk factors [(adjusted OR 1.36; 95%CI (1.13–1.63)]. Such predictive value of low level HDL-C persisted even when LDL-C was at very low level(<1.8 mmol/L). Patients in the lowest serum HDL-C quartile (<0.96 mmol/L) had the highest risk of developing ICAS [adjusted OR 1.52; 95%CI (1.17–1.98)] compared to patients in the highest serum HDL-C quartile (≥1.32 mmol/L) after adjustments for the covariates.ConclusionsLow HDL-C level is strongly associated with the development of ICAS. There was an inverse relationship between the level of HDL-C and the risk of developing ICAS.

Adhesion molecules CD146 and its soluble form strongly correlated with the development of inflammation of atherosclerosis and plaque instability. CD146 may be a promising biomarker for monitoring the development and instability of atherosclerotic plaque in patients with carotid diseases.