title: PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRα through the IGF-I-mediated signaling pathway.
abstract: Pregnancy-associated plasma protein-A (PAPP-A) has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of the phosphatidylinositol-3 (PI3-K) and Akt kinase (Akt) signaling cascades which lead to constitutive nitric oxide formation, with its attending vasodilator, antiplatelet and insulin-sensitizing actions. In addition, IGF-1 may decreased cholesterol efflux through reductions of expression in ABCA1 and SR-B1 by the PI3-K/Akt signaling pathway. In the current study, we examined whether PAPP-A was involved in LXRα regulation and in expression of ABCA1, ABCG1 or SR-B1 through the IGF-I-mediated signaling pathway (IGF/PI3-K/Akt). Results showed that PAPP-A significantly decreased expression of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by PAPP-A treatment. Moreover, LXRα which can regulate the expression of ABCA1, ABCG1 and SR-B1, was also down-regulated by PAPP-A treatment. LXRα-specific activation by LXRα agonist almost rescued the down-regulation of ABCA1, ABCG1 and SR-B1 expression by PAPP-A. In addition, PAPP-A can induce the IGF-1/PI3-K/Akt pathway in macrophages. Furthermore, our results indicate that the decreased levels observed in LXRα, ABCA1, ABCG1 and SR-B1 mRNA and protein levels upon treating cells with PAPP-A were strongly impaired with the PI3-K inhibitors or IGF-1R siRNA while the MAPK cascade inhibitor did not execute this effect, indicating that the process of ABCA1, ABCG1 and SR-BI degradation by PAPP-A involves the IGF-1/PI3-K/Akt pathway. In conclusion, PAPP-A may first down-regulate expression of LXRα through the IGF-1/PI3-K/Akt signaling pathway and then decrease expression of ABCA1, ABCG1, SR-B1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study provided one of the mechanisms for understanding the critical effect of PAPP-A in pathogenesis of atherosclerosis.
authors.affiliation: Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.
authors.forename: Shi-Lin
authors.initials: SL
authors.lastname: Tang
authors.forename: Wu-Jun
authors.initials: WJ
authors.lastname: Chen
authors.forename: Kai
authors.initials: K
authors.lastname: Yin
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Zhao
authors.forename: Zhong-Cheng
authors.initials: ZC
authors.lastname: Mo
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Lv
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Ouyang
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Yu
authors.forename: Huai-Jun
authors.initials: HJ
authors.lastname: Kuang
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Jiang
authors.forename: Yu-Chang
authors.initials: YC
authors.lastname: Fu
authors.forename: Chao-Ke
authors.initials: CK
authors.lastname: Tang
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D015536:Down-Regulation; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D011266:Pregnancy-Associated Plasma Protein-A