Purpose: Studies have shown that nifedipine protects against atherosclerotic progression, but its underlying mechanisms remain unclear. In this study, we examined if nifedipine increases macrophage cholesterol efflux, a pathway known to inhibit atherogenesis.
Methods: We evaluated the ability of different doses of nifedipine to affect cholesterol efflux in RAW264.7 macrophages and its relationship with mRNA and protein levels of several well-characterized proteins involved in cholesterol efflux, including ABCA1, ABCG1, SR-BI and LXRα, using quantitative real-time PCR, Western blotting, and siRNA techniques.
Results: Nifedipne at 1, 10, and 100 nmol/L increased apoA-I-mediated cholesterol efflux from 2.55 % to 5.65 %, 6.20 %, and 6.10 %, as well as HDL-mediated cholesterol efflux from 31.0 % to 42.5 %, 46.0 %, and 43.5 %, respectively, in RAW264.7 macrophages (p < 0.05), which was associated with increased mRNA expression levels of ABCA1, ABCG1, SR-BI, and LXRα (405 %, 381 %, 336 %; 890 %, 960 %, 1002 %; 285 %, 325 %, 336 %; 482 %, 445 %, 405 %, respectively, p < 0.05), and with increased protein levels of ABCA1, ABCG1, SR-BI, and LXRα (428 %, 492 %, 361 %; 288 %, 331 %, 365 %; 283 %, 320 %, 505 %; 581 %, 678 %, 608 %, respectively, p < 0.05). SiRNA-mediated silencing of LXRα revealed that LXRα was involved in these increases and the enhanced cholesterol efflux.
Conclusion: Nifedipine may protect against atherosclerosis partly by promoting macrophage cholesterol efflux through the stimulation of LXRα-dependent expression of ABCA1, ABCG1, and SR-BI.