Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma.
OBJECTIVE
The ATP binding cassette transporters A1 and G1 (ABCA1/G1) and scavenger receptor class B type I (SR-BI) are key molecules in cholesterol efflux and atherogenesis. These genes are regulated by peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor (LXR). Telmisartan is an angiotensin type 1 receptor blocker which has been reported to act as a ligand for PPARgamma. We investigated whether PPARgamma-activating ARBs affect the expression of these genes and cholesterol efflux from macrophages.


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 PPARgamma by siRNA abolished the telmisartan-induced expression of these genes. The knockdown of LXRalpha 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 PPARgamma pathway but not on the LXRalpha 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.


CONCLUSIONS
Our results showed that telmisartan enhanced both apoA-I- and HDL-mediated cholesterol efflux from macrophages by increasing ABCA1, ABCG1 and SR-BI expression via PPARgamma-dependent and LXR-dependent/independent pathways.
Nakaya
Kazuhiro
K
Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
Ayaori
Makoto
M
Hisada
Tetsuya
T
Sawada
Shojiro
S
Tanaka
Nobukiyo
N
Iwamoto
Noriyuki
N
Ogura
Masatsune
M
Yakushiji
Emi
E
Kusuhara
Masatoshi
M
Nakamura
Haruo
H
Ohsuzu
Fumitaka
F
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D000077333:Telmisartan
D018528:ATP-Binding Cassette Transporters; D000806:Angiotensin-Converting Enzyme Inhibitors; D016632:Apolipoprotein A-I; D001562:Benzimidazoles; D001565:Benzoates; D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D000077333:Telmisartan