Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells.
Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells.
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DOI：
10.3390/cimb44110370
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发表时间：
2022-11-03
影响因子：
3.1
通讯作者：
Murao, Koji
中科院分区：
文献类型：
--
作者：
Lyu, Jingya;Imachi, Hitomi;Fukunaga, Kensaku;Sato, Seisuke;Kobayashi, Toshihiro;Saheki, Takanobu;Japar, Salimah;Iwama, Hisakazu;Matsumura, Yuta;Ozaki, Miyo;Yoshimura, Takafumi;Murao, Koji
胰高血糖素样肽-1受体激动剂（GLP-1 RA）已被临床证明可以保护内皮功能。以前，我们证明，内皮NO合酶（eNOS）激活高密度脂蛋白（HDL）通过其清道夫受体的B类/人类同源物SR-BI，CD 36和LIMPII类似物-1（hSR-BI/CLA-1）。在此，我们研究了GLP-1 RA和exendin-4对HUVECs中hSR-BI/CLA-1表达的影响。我们的研究结果证实，GLP-1 R的表达在HUVECs通过PCR和exendin-4显着增强HDL诱导的eNOS激活。接下来，exendin-4增加hSR-BI/CLA-1的表达，GLP-1 R的阻断消除了这种作用。此外，exendin-4可增强hSR-BI/CLA-1的转录活性，而AMPK或显性负性AMPK-α-亚基的抑制可减弱该活性。此外，AMPK通过GLP-1 R的活化而磷酸化。接下来，ChIP测定证明毒蜥外泌肽-4通过上调FoxO 1增加hSR-BI/CLA-1启动子中的FoxO 1结合。FoxO 1结合的突变或FoxO 1的沉默取消了exendin-4对hSR-BI/CLA-1表达的影响。Exendin-4可降低FoxO 1的磷酸化并诱导其在细胞核内蓄积，而阻断GLP-1 R或抑制AMPK通路可改变这种作用。总之，我们的结果证明exendin-4通过AMPK/FoxO 1途径增加hSR-BI/CLA-1表达以激活eNOS，提供了强调GLP-1 RA对内皮功能的保护作用的基本机制。
Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been clinically proven to protect endothelial function. Previously, we demonstrated that endothelial NO synthase (eNOS) was activated by high-density lipoprotein (HDL) via its scavenger receptor of the B class/human homologue of SR-BI, CD36 and LIMPII analogous-1(hSR-BI/CLA-1). Here, we investigated the effect of GLP-1RA and exendin-4 on the expression of hSR-BI/CLA-1 in HUVECs. Our results confirmed that GLP-1R was expressed in HUVECs by PCR and exendin-4 significantly enhanced HDL-induced eNOS activation. Next, exendin-4 increased the expression of hSR-BI/CLA-1 and a blockade of GLP-1R cancelled this effect. Further, the hSR-BI/CLA-1 transcriptional activity was enhanced by exendin-4, which was diminished by the inhibition of AMPK or dominant-negative AMPK-α-subunit. Moreover, AMPK was phosphorylated by the activation of GLP-1R. Next, ChIP assay demonstrated that exendin-4 increased the FoxO1-binding in the hSR-BI/CLA-1 promoter by upregulation of FoxO1. Mutation of FoxO1-binding or silencing of FoxO1 cancelled the effect of exendin-4 on hSR-BI/CLA-1 expression. Exendin-4 reduced FoxO1 phosphorylation and induced its nuclear accumulation, while this effect was altered by the blocking of GLP-1R or inhibition of AMPK pathway. In summary, our results proved that exendin-4 increased hSR-BI/CLA-1 expression via the AMPK/FoxO1 pathway to activate eNOS, providing a basic mechanism underlining the protective effect of GLP-1RA on endothelial function.
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影响因子：
5.9
作者：
Ibata T;Lyu J;Imachi H;Fukunaga K;Sato S;Kobayashi T;Saheki T;Yoshimura T;Murao K
通讯作者：
Murao K
DOI：
10.2337/ds16-0026
发表时间：
2017-08-01
期刊：
Diabetes spectrum : a publication of the American Diabetes Association
影响因子：
--
作者：
Hinnen, Deborah
通讯作者：
Hinnen, Deborah
影响因子：
9.3
作者：
Simó R;Guerci B;Schernthaner G;Gallwitz B;Rosas-Guzmàn J;Dotta F;Festa A;Zhou M;Kiljański J
通讯作者：
Kiljański J
影响因子：
4.7
作者：
通讯作者：
--
影响因子：
4.8
作者：
Murao, K;Terpstra, V;Quehenberger, O
通讯作者：
Quehenberger, O