Cyclophilin D induces necrotic core formation by promoting mitochondria-mediated macrophage apoptosis in advanced atherosclerotic lesions

BackgroundIn advanced atherosclerotic lesions, apoptotic cell death of plaque macrophages results in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. MethodsTo clarify the specific role of CypD, apolipoprotein-E/CypD-double knockout (ApoE-/-CypD-/-) mice were generated. These mice were fed a high-fat diet containing 0.15% cholesterol for 24 weeks to accelerate atherosclerotic lesion development. ResultsThe deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control ApoE-/- mice. In RAW264.7 cells treated with endoplasmic reticulum stress inducer thapsigargin, the release of cytochrome c to the cytosol was attenuated by siRNA-mediated knockdown of CypD. Ly-6Chigh inflammatory monocytes in the peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by the deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-{gamma}, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. ConclusionsThis is the first report showing that CypD induces macrophage death and promotes necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.