Dataset Information

Cavin-1 regulates caveolae-mediated LDL transcytosis: crosstalk in an AMPK/eNOS/ NF-?B/Sp1 loop.

ABSTRACT: Caveolae are specialized lipid rafts structure in the cell membrane and critical for regulating endothelial functions, e.g. transcytosis of macromolecules like low density lipoprotein (LDL) etc. Specifically, the organization and functions of caveolae are mediated by structure protein (caveolin-1) and adapter protein (cavin-1). The pathogenic role of caveolin-1 is well studied; nevertheless, mechanisms whereby cavin-1 regulates signaling transduction remain poorly understood. The aim of this study was designed to explore the role of cavin-1 in caveolae-mediated LDL transcytosis across endothelial cells. We reported here that cavin-1 knockdown mediated by small interfering RNA (siRNA) caused a significant decrease of LDL transcytosis. Moreover, cavin-1 knockdown increased the activity of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide (NO). Consequently, an eNOS inhibitor, N-Nitro-L-Arginine Methyl Ester (L-NAME), not only suppressed the activity of specificity protein (Sp1) and nuclear factor kappa B (NF-?B), but also inhibited both activities via activating adenosine 5'-monophosphate- activated protein kinase (AMPK). In conclusion, we proposed an AMPK/eNOS/NF-?B/Sp1 circuit loop was formed to regulate caveolae residing proteins' expression, e.g. LDL receptor (LDLR), caveolin-1, eNOS, thereby to regulate caveolae-mediated LDL transcytosis in endothelial cells.

SUBMITTER: Bai XL

PROVIDER: S-EPMC5732781 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Cavin-1 regulates caveolae-mediated LDL transcytosis: crosstalk in an AMPK/eNOS/ NF-κB/Sp1 loop.

Bai Xiang-Li XL Yang Xiao-Yan XY Li Ju-Yi JY Ye-Li Jia Xiong X Xiong Zhi-Fan ZF Wang Yu-Mei YM Jin Si S

Oncotarget 20171019 61

Caveolae are specialized lipid rafts structure in the cell membrane and critical for regulating endothelial functions, <i>e.g.</i> transcytosis of macromolecules like low density lipoprotein (LDL) <i>etc</i>. Specifically, the organization and functions of caveolae are mediated by structure protein (caveolin-1) and adapter protein (cavin-1). The pathogenic role of caveolin-1 is well studied; nevertheless, mechanisms whereby cavin-1 regulates signaling transduction remain poorly understood. The a ...[more]

PMID: 29262615

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Project description:Thiazolidinediones, the antidiabetic agents such as ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that ciglitazone, the PPAR? agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by ciglitazone. Of interest, AMPK inhibition abolished ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPAR? significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by ciglitazone, but re-enhanced by blocking PPAR? or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that ciglitazone-mediated PPAR? activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.

Dataset Information

Cavin-1 regulates caveolae-mediated LDL transcytosis: crosstalk in an AMPK/eNOS/ NF-?B/Sp1 loop.

Publications

Cavin-1 regulates caveolae-mediated LDL transcytosis: crosstalk in an AMPK/eNOS/ NF-κB/Sp1 loop.

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