Abstract
Type 2 diabetes (T2D) is associated with accelerated atherosclerosis, which accounts for approximately 75% of all diabetes-related deaths. Here we investigate the link between diabetes and macrophage cholesteryl ester accumulation. When diabetic (db/db) mice are given cholesteryl ester intraperitoneally (IP), peritoneal macrophages (PerMΦs) recovered from these animals showed a 58% increase in intracellular cholesteryl ester accumulation over PerMΦs from heterozygote control (db/+) mice. Notably, PerMΦ fluid-phase endocytosis and large particle phagocytosis was equivalent in db/+and db/db mice. However, IP administration of CD36 and SR-A blocking antibodies led to 37% and 25% reductions in cholesteryl ester accumulation in PerMΦ. Finally, in order to determine if these scavenger receptors (SRs) were part of the mechanism responsible for the increased accumulation of cholesteryl esters observed in the diabetic mouse macrophages, receptor expression was quantified by flow cytometry. Importantly, db/db PerMΦs showed a 43% increase in CD36 expression and an 80% increase in SR-A expression. Taken together, these data indicate that direct cholesteryl ester accumulation in mouse macrophages is mediated by CD36 and SR-A, and the magnitude of accumulation is increased in db/db macrophages due to increased scavenger receptor expression.
Highlights
Type 2 diabetes (T2D) is an independent risk factor for developing atherosclerosis [1]
To determine if AcLDL or cholesteryl ester uptake was affected by diabetes, we examined resident PerMWs from db/db and db/+mice
We found that PerMWs from db/db mice have increased AcLDL uptake compared to db/+controls (Fig. 1A)
Summary
T2D is an independent risk factor for developing atherosclerosis [1]. Patients with T2D are 2 to 4 times more likely to develop atherosclerosis [3]. Dyslipidemia, hypertension, oxidation state, endothelial cell function, hyperglycemia, insulin resistance, and advanced glycation end-products (AGEs) have been shown to play a role in diabetes-accelerated atherosclerosis [5][6][7]. It has not been determined if direct cholesteryl ester uptake by macrophages and subsequent foam cell formation may be altered in the diabetic state contributing to diabetesaccelerated atherosclerosis
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