Amelioration of the foam cell formation by simvastatin due to increased expression of Niemann‐Pick disease type C1 protein and enhanced lysosomal lipids transport (606.4)

It is well accepted that statins, hypercholesterol‐lowing agents, have direct therapeutic effects on the atherosclerotic lesions. However, the underlying mechanism remains unknown. Given the pivotal role of macrophages in atherosclerosis, the present study was designed to investigate the effects of simvastatin, a prototype of the most statins used clinically, on the foam cell formation by examining lysosomal lipids in macrophages. Using fluorescent microplate reader and confocal microscopy, we found that simvastatin dose‐dependently (in nM: 0, 10, 50, 100, 150 and 200) decreased lysosomal lipid deposition in macrophages treated with oxLDL ( 40 µg/ml ) as stained by lysosomal lipid specific dye of Bodipy 493/503. Oil red O staining and electron microscopy showed that the foam cell formation was substantially attenuated. In simvastatin‐ treated macrophages, the cholesterol level in the purified lysosome fractions was markedly decreased. RT‐PCR analysis revealed that the expression of NPC1, a lysosomal cholesterol transporter, was significantly enhanced. Silencing of NPC1 markedly decreased simvastatin‐induced lysosomal lipids transport. These results indicate that simvastatin‐induced cholesterol transport out of lysosome in macrophages leads to foam cell formation attenuation via enhancing NPC1 expression, which may be a therapeutic mechanism of statins to ameliorate atherosclerotic lesions. Grant Funding Source : NIH R01HL115068