Telmisartan enhances cholesterol eff lux from THP-1 macrophages by activating PPARγ

Aim: The ATP binding cassette transporters A1 and G1 (ABCA1/G1) and scavenger receptor class B type I (SR-B I) are key molecules in cholesterol efflux and atherogenesis. These genes are regulated by peroxisome proliferator-activated receptor gamma (PPAR gamma) and liver X receptor (LY-R). Telmisartan is an angiotensin type I receptor blocker which has been reported to act as a ligand for PPAR gamma. We investigated whether PPAR gamma-activating ARBs affect the expression of these genes and cholesterol efflux from macrophages. Methods and Results: Telmisartan increased ABCA1, ABCG1 and SR-B I mRNA levels in THP-1 macrophages in a dose- and time-dependent fashion. It also increased their protein levels and enhanced apoA-I- and HDL-mediated cholesterol efflux from macrophages. The knockdown of PPAR gamma by siRNA abolished the telmisartan-induced expression of these genes. The knockdown of LXR alpha resulted in the complete and partial abolishment of telmisartan-induced ABCA1 and ABCG1 expression, respectively. We also demonstrated that telmisartan-induced SR-B I expression was dependent on the PPAR gamma pathway but not on the LYR alpha pathway. A luciferase assay using an ABCA1 promoter construct showed that telmisartan activated ABCA1 transcription, which was abolished if the LXR binding element was mutated, indicating that increased ABCA1 transcription by telmisartan is LXR-dependent. Conclusion: Our results showed that telmisartan enhanced both apoA-I- and HDL-mediated cholesterol efflux from macrophages by increasing ABCA1, ABCG1 and SR-B I expression via PPAR gamma-dependent and LXR-dependent/independent pathways.