Nakaya Kazuhiro, Ayaori Makoto, Hisada Tetsuya, Sawada Shojiro, Tanaka Nobukiyo, Iwamoto Noriyuki, Ogura Masatsune, Yakushiji Emi, Kusuhara Masatoshi, Nakamura Haruo, Ohsuzu Fumitaka
Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
J Atheroscler Thromb. 2007 Jun;14(3):133-41. doi: 10.5551/jat.14.133.
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.
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.
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.
ATP结合盒转运体A1和G1（ABCA1/G1）以及B1型清道夫受体（SR-BI）是胆固醇流出和动脉粥样硬化形成中的关键分子。这些基因受过氧化物酶体增殖物激活受体γ（PPARγ）和肝X受体（LXR）调控。替米沙坦是一种血管紧张素1型受体阻滞剂，据报道可作为PPARγ的配体。我们研究了激活PPARγ的ARB是否会影响这些基因的表达以及巨噬细胞的胆固醇流出。
替米沙坦以剂量和时间依赖性方式增加THP-1巨噬细胞中ABCA1、ABCG1和SR-BI的mRNA水平。它还增加了它们的蛋白质水平，并增强了载脂蛋白A-I和高密度脂蛋白介导的巨噬细胞胆固醇流出。通过小干扰RNA敲低PPARγ可消除替米沙坦诱导的这些基因的表达。敲低LXRα分别导致替米沙坦诱导的ABCA1和ABCG1表达完全和部分被消除。我们还证明，替米沙坦诱导的SR-BI表达依赖于PPARγ途径而非LXRα途径。使用ABCA1启动子构建体的荧光素酶测定表明，替米沙坦激活了ABCA1转录，如果LXR结合元件发生突变，这种激活就会被消除，这表明替米沙坦增加ABCA1转录是依赖LXR的。
我们的结果表明，替米沙坦通过PPARγ依赖性和LXR依赖性/非依赖性途径增加ABCA1、ABCG1和SR-BI的表达，从而增强载脂蛋白A-I和高密度脂蛋白介导的巨噬细胞胆固醇流出。
