title: MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport-An anti-atherogenic function of ERK1/2 inhibition.
abstract: Expression of ATP-binding cassette transporter G1 (ABCG1), a molecule facilitating cholesterol efflux to HDL, is activated by liver X receptor (LXR). In this study, we investigated if inhibition of ERK1/2 can activate macrophage ABCG1 expression and functions. MEK1/2 inhibitors, PD98059 and U0126, increased ABCG1 mRNA and protein expression, and activated the natural ABCG1 promoter but not the promoter with the LXR responsive element (LXRE) deletion. Inhibition of ABCG1 expression by ABCG1 siRNA did enhance the formation of macrophage/foam cells and it attenuated the inhibitory effect of MEK1/2 inhibitors on foam cell formation. MEK1/2 inhibitors activated macrophage cholesterol efflux to HDL in vitro, and they enhanced reverse cholesterol transport (RCT) in vivo. ApoE deficient (apoE(-/-)) mice receiving U0126 treatment had reduced sinus lesions in the aortic root which was associated with activated macrophage ABCG1 expression in the lesion areas. MEK1/2 inhibitors coordinated the RXR agonist, but not the LXR agonist, to induce ABCG1 expression. Furthermore, induction of ABCG1 expression by MEK1/2 inhibitors was associated with activation of SIRT1, a positive regulator of LXR activity, and inactivation of SULT2B1 and RIP140, two negative regulators of LXR activity. Taken together, our study suggests that MEK1/2 inhibitors activate macrophage ABCG1 expression/RCT, and inhibit foam cell formation and lesion development by multiple mechanisms, supporting the concept that ERK1/2 inhibition is anti-atherogenic.
authors.affiliation: Department of Cardiology, Xijing Hospital, the 4th Military Medical University, Xi'an, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; School of Medicine, Nankai University, Tianjin, China.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xingyue
authors.initials: X
authors.lastname: Cao
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Pharmacy, Nankai University, Tianjin, China.
authors.forename: Luyuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Qing Robert
authors.initials: QR
authors.lastname: Miao
authors.affiliation: Weill Cornell Medical College, New York, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Hajjar
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin, China. Electronic address: yduan@hfut.edu.cn.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin, China. Electronic address: hanjihong2015@hfut.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics*; D002070:Butadienes / Q000008:administration & dosage; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000008:administration & dosage; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000071518:Liver X Receptors / Q000096:biosynthesis / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles / Q000008:administration & dosage; D011401:Promoter Regions, Genetic; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000235:genetics; D056564:Sirtuin 1 / Q000096:biosynthesis
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D001057:Apolipoproteins E; D002070:Butadienes; D005419:Flavonoids; D000071518:Liver X Receptors; D009570:Nitriles; D047490:Retinoid X Receptor alpha; C113580:U 0126; D002784:Cholesterol; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ABCG1; Atherosclerosis; LXR; MEK1/2; RCT; SIRT1