Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms.
Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms.
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DOI：
10.1038/s41598-018-23420-4
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发表时间：
2018-03-27
影响因子：
4.6
通讯作者：
Salt IP
中科院分区：
文献类型：
--
作者：
Mancini SJ;Boyd D;Katwan OJ;Strembitska A;Almabrouk TA;Kennedy S;Palmer TM;Salt IP
最近的降血糖钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂的临床试验报告了有益的心血管结局，该抑制剂抑制肾脏葡萄糖重吸收。然而，SGLT2 抑制剂是否直接影响心血管组织仍不清楚。我们之前报道过 SGLT2 抑制剂卡格列净可激活永生化细胞系和小鼠肝细胞中的 AMP 激活蛋白激酶 (AMPK)。由于 AMPK 在血管细胞中具有抗炎作用，我们检查了 SGLT2 抑制剂是否减弱培养的人内皮细胞中的炎症信号传导。与临床相关浓度的卡格列净一起孵育，但恩格列净或达格列净不会激活 AMPK，并抑制 IL-1β 刺激的前单核细胞 U937 粘附以及 IL-6 和单核细胞趋化蛋白 1 (MCP-1) 的分泌。 MCP-1 分泌的抑制因显性失活 AMPK 的表达而减弱，并且可被直接 AMPK 激活剂 A769662 模拟。用卡格列净或 A769662 刺激细胞对 IL-1β 刺激的细胞表面粘附分子或核因子 κB 信号传导水平没有影响。尽管卡格列净和 A769662 具有相同的作用，IL-1β 刺激的 IL-6/MCP-1 mRNA 被卡格列净抑制，但 A769662 不被抑制，而 IL-1β 刺激的 c-jun N 末端激酶磷酸化被 A769662 抑制，但卡格列净不被抑制。这些数据表明，临床相关的卡格列净浓度通过 AMPK 依赖性和非依赖性机制直接抑制内皮促炎趋化因子/细胞因子分泌，而不影响早期 IL-1β 信号传导。
Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.
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影响因子：
3.7
作者：
Oelze M;Kröller-Schön S;Welschof P;Jansen T;Hausding M;Mikhed Y;Stamm P;Mader M;Zinßius E;Agdauletova S;Gottschlich A;Steven S;Schulz E;Bottari SP;Mayoux E;Münzel T;Daiber A
通讯作者：
Daiber A
DOI：
10.1152/ajplung.00167.2015
发表时间：
2015-11-01
影响因子：
4.9
作者：
Han, Ying;Cho, Young-Eun;Makino, Ayako
通讯作者：
Makino, Ayako
影响因子：
7.7
作者：
Joubert, Michael;Jagu, Benoit;Prieur, Xavier
通讯作者：
Prieur, Xavier
影响因子：
3.8
作者：
Brand, Tobias;Macha, Sreeraj;Woerle, Hans J.
通讯作者：
Woerle, Hans J.
血管内皮细胞通过被动扩散和 SGLT1 介导的途径吸收白藜芦醇
影响因子：
5.6
作者：
Chen, Ming-liang;Yi, Long;Mi, Man-tian
通讯作者：
Mi, Man-tian