Telmisartan enhances cholesterol efflux 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-B1) are key molecules in cholesterol efflux and atherogenesis. These genes are regulated by peroxisome proliferator-activated receptor y (PPARy) and liver X receptor (LXR). Telmisartan is an angiotensin type 1 receptor Rocker which has been reported to act as a ligand for PPARy. We investigated whether PPARy -activating ARBs affect the expression of these genes and cholesterol efflux from macrophages. Methods and Results: Telmisartan increased ABCA1, ABCG1 and SR-BI 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 PPARy by siRNA abolished the telmisartan-induced expression of these genes. The knockdown of LXRa resulted in the complete and partial abolishment of telmisartan-induced ABCA1 and ABCG1 expression, respectively. We also demonstrated that telmisartan-induced SR-BI expression was dependent on the PPARy pathway but not on the LXRa 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-B1 expression via PPARy -dependent and LXR-dependent/ independent pathways.