CD36-Dependent 7-Ketocholesterol Accumulation in Macrophages Mediates Progression of Atherosclerosis in Response to Chronic Air Pollution Exposure

Abstract

Rationale Air pollution exposure has been shown to potentiate plaque progression in humans and animals. Our previous studies have suggested a role for oxidized lipids in mediating adverse vascular effect of air pollution. However, the types of oxidized lipids formed in response to air pollutants and how this occurs and their relevance to atherosclerosis is not fully understood. Objective To investigate the mechanisms by which particulate matter< 2.5μm (PM2.5) induces progression of atherosclerosis. Methods and Results Atherosclerosis-prone ApoE−/− or LDLR−/− mice were exposed to filtered air or concentrated ambient PM2.5 using a versatile aerosol concentrator enrichment system for 6 months. PM2.5 increased 7-ketocholesterol (7-KCh), an oxidatively modified form of cholesterol, in plasma IDL/LDL fraction and in aortic plaque concomitant with progression of atherosclerosis and increased CD36 expression in plaque-macrophages from PM2.5-exposed mice. Macrophages isolated from PM2.5-exposed mice displayed increased uptake of oxidized lipids without alterations in their efflux capacity. Consistent with these finding, CD36-positive macrophages displayed a heightened capacity for oxidized lipid uptake. Deficiency of CD36 on hematopoietic cells diminished the effect of air pollution on 7-KCh accumulation, foam cell formation, and atherosclerosis. Conclusions Our results suggest a potential role for CD36-mediated abnormal accumulations of oxidized lipids such as 7-KCh in air pollution induced atherosclerosis progression.

Detection and confirmation of serum lipid biomarkers for preeclampsia using direct infusion mass spectrometry

“…For example, among the several markers, the peak at m/z 383.3 was predicted to be an oxidized cholesterol (keto or epoxy). The 7-ketocholesterol, which has the same mass, has been proposed to contribute to atherosclerosis ( 48 ), and vascular changes similar to atherosclerotic disease have been reported in preeclampsia ( 49 ). This might explain the higher levels of this marker observed in women with later preeclampsia.…”

Endothelial inflammatory transcriptional responses to an altered plasma exposome following inhalation of diesel emissions

“…Vascular inflammation and metabolic syndrome plays a substantial role as a substrate for autoimmunity. The proatherogenic environment supports development of autoimmunity via TH17 differentiation, in a manner dependent on CD36 (Lim, Kim et al 2014), a scavenger receptor that is activated by certain air pollutant exposures (Robertson, Colombo et al 2013, Rao, Zhong et al 2014). In the present study, we observed clusters of activated transcripts that control secreted proteins involved in common chronic diseases such as inflammatory bowel disease (WNT6), osteoarthritis (ADAMTS5, LTBP3), and connective tissue homeostasis (COL12A1).…”

“…Probing the transcriptional responses provides clues as to what the compositionally altered plasma may activate in endothelial cells, but whether such changes are sufficient to impact homeostasis remains unclear. Based on recent findings of roles for multiligand receptors LOX-1 (Lund, Lucero et al 2011), TLR4 (Kampfrath, Maiseyeu et al 2011), and CD36 (Robertson, Colombo et al 2013, Rao, Zhong et al 2014), all of which could generate a portion of the inflammatory signaling responses observed in the plasma-treated endothelial cells (Silverstein and Febbraio 2009, Sikorski, Czerwoniec et al 2011, Pirillo, Norata et al 2013), ligands to such receptors are a likely intermediate that could be assessed in future research.…”

Basic mechanisms for adverse cardiovascular events associated with air pollution

“…Long term exposure to CAPs has been shown to promote experimental atherosclerosis in two different mouse models through increased CD36 expression in plaque macrophages that facilitates greater uptake and accumulation of an oxidised form of cholesterol in atherosclerotic lesions. 20 Chronic CAP exposure also promotes inflammatory monocyte egress from bone marrow, production of reactive oxygen species, and subsequent vascular dysfunction through TLR4 activation of NADPH oxidase in mice. 10 Controlled exposure in human subjects has also been shown to promote vascular dysfunction acutely through alteration of responsiveness to vasoactive mediators, to reduce endogenous fibrinolysis, and also to enhance exercise induced myocardial ischaemia in patients with coronary disease.…”