PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXR伪 through the IGF-I-mediated signaling pathway

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• 作者：Shi-Lin Tang^a ; ^b ; ¹ ; Wu-Jun Chen^a ; ^c ; ¹ ; Kai Yin^a ; Guo-Jun Zhao^a ; Zhong-Cheng Mo^a ; Yun-Cheng Lv^a ; Xin-Ping Ouyang^a ; Xiao-Hua Yu^a ; Huai-Jun Kuang^a ; ^d ; Zhi-Sheng Jiang^a ; Yu-Chang Fu^e ; Chao-Ke Tang^a ; ^{tchaoke@yahoo.com.cn}
• 关键词：PAPP-A ; pregnancy-associated plasma protein-A ; IGF-1 ; insulin-like growth factor 1 ; IGF-1R ; insulin-like growth factor 1 receptor ; PI3-K ; phosphatidylinositol 3-kinase ; Akt ; Akt kinase or protein kinase B (PKB) ; ABCA1 ; ATP-binding cassette transporter A1
• 刊名：Atherosclerosis
• 出版年：2012
• 期刊代码：28_00219150
• 类别：med
• 出版时间：June, 2012
• 卷：222
• 期：2
• 页码：344-354
• 文件大小：1187 K

摘要

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 LXR伪 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, LXR伪 which can regulate the expression of ABCA1, ABCG1 and SR-B1, was also down-regulated by PAPP-A treatment. LXR伪-specific activation by LXR伪 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 LXR伪, 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 LXR伪 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.