RRC ID 43016
著者 Nakaya K, Ayaori M, Hisada T, Sawada S, Tanaka N, Iwamoto N, Ogura M, Yakushiji E, Kusuhara M, Nakamura H, Ohsuzu F.
タイトル Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma.
ジャーナル J Atheroscler Thromb
Abstract AIM: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.
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 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.
CONCLUSION: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.
巻・号 14(3)
ページ 133-41
公開日 2007-6-1
DOI 10.5551/jat.14.133
PII JST.JSTAGE/jat/14.133
PMID 17587765
MeSH ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / metabolism Angiotensin-Converting Enzyme Inhibitors / pharmacology* Apolipoprotein A-I / genetics Apolipoprotein A-I / metabolism Benzimidazoles / pharmacology* Benzoates / pharmacology* Cells, Cultured Cholesterol / metabolism* DNA-Binding Proteins / antagonists & inhibitors DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Gene Expression Regulation* Humans Lipoproteins, HDL / metabolism Liver X Receptors Macrophages / drug effects* Macrophages / metabolism Orphan Nuclear Receptors PPAR gamma / antagonists & inhibitors PPAR gamma / genetics PPAR gamma / metabolism* RNA, Small Interfering / pharmacology Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors Receptors, Cytoplasmic and Nuclear / genetics Receptors, Cytoplasmic and Nuclear / metabolism Scavenger Receptors, Class B / genetics Scavenger Receptors, Class B / metabolism Telmisartan
IF 3.876
引用数 52
WOS 分野 PERIPHERAL VASCULAR DISEASE
リソース情報
ヒト・動物細胞