Induction of CD36 by all‐trans retinoic acid: retinoic acid receptor signaling in the pathogenesis of atherosclerosis

Scavenger receptors mediating the uptake of oxidized low‐density lipoproteins (oxLDL) by macrophages play a crucial role in foam cell formation during atherosclerosis. One member of this receptor family, the thrombospondin receptor CD36, has recently been shown to mediate a major part of the oxLDL‐induced aggravation of atherosclerotic lesions. Here, we show that the expression of CD36 protein and mRNA in human monocytic THP‐1 cells is increased by all‐trans retinoic acid (atRA), a derivative of the essential Vitamin A, which leads to increased uptake of oxLDL. CD3106, a specific antagonist at the retinoic acid receptor (RAR), inhibited the atRA‐induced CD36 expression, whereas the RAR‐specific agonist CD367 induced CD36 to the same degree as atRA. This indicates an RAR‐mediated CD36 induction. AtRA and oxLDL had synergistic effects in up‐regulating CD36 when in both THP‐1 cells and primary monocytes. Applying a sensitive RAR‐GAL‐4 reporter assay, we could demonstrate RAR ligands in human atherosclerotic lesions. In addition, immunohistochemistry showed RAR‐α and ‐γ in the lesions, which indicates that atRA may contribute to foam cell formation and the progress of atherosclerosis.