LncRNA ENSMUST00000155383 is Involved in the Improvement of DPP-4 Inhibitor MK-626 on Vascular Endothelial Function by Modulating Cacna1c-Mediated Ca(2+) Influx in Hypertensive Mice.
LncRNA ENSMUST00000155383 is Involved in the Improvement of DPP-4 Inhibitor MK-626 on Vascular Endothelial Function by Modulating Cacna1c-Mediated Ca(2+) Influx in Hypertensive Mice.
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LncRNA ENSMUST00000155383 通过调节 Cacna1c 介导的 Ca2+ 流入，参与高血压小鼠 DPP-4 抑制剂 MK-626 对血管内皮功能的改善
DOI：
10.3389/fmolb.2021.724225
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发表时间：
2021
影响因子：
5
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Zhang Y;Tan N;Zong Y;Li L;Zhang Y;Liu J;Wang X;Han W;Liu L
目的：本研究探讨二肽基肽酶 4 抑制剂 MK-626 通过调节高血压血管系统中的 lncRNA 对血管内皮功能的保护作用。 方法：将血管紧张素Ⅱ（Ang Ⅱ）负载的渗透泵植入小鼠体内，给予或不给予MK-626。通过ELISA测定血浆中的GLP-1水平。主动脉环悬挂在肌动描记器中进行张力测量。进行微阵列分析 lncRNA 和 mRNA 表达谱。通过蛋白质印迹检查蛋白质表达和磷酸化。通过 qRT-PCR 验证差异表达 (DE) 基因。采用激光共聚焦系统检测细胞内Ca2+浓度。 结果：MK-626 提高 Ang Ⅱ 诱导的高血压小鼠血浆 GLP-1 水平，增加 eNOS 磷酸化，改善内皮依赖性舒张，降低收缩压。微阵列显示高血压小鼠主动脉中 723 个 lncRNA 和 742 个 mRNA 的失调被 MK-626 逆转。 qRT-PCR 验证显示，高血压小鼠主动脉和小鼠主动脉内皮细胞 (MAEC) 中的 13 个 DE-lncRNA 和 8 个失调的 mRNA 被 MK-626 拯救。其中，4个mRNA（Cacna1C、Itgav、Itga8和Npnt）与lncRNA ENSMUST00000155383共表达。 Ang Ⅱ输注小鼠的 EC 中 Cacna1C 蛋白表达降低，而平滑肌细胞中 Cacna1C 蛋白表达升高，而这两种情况均被 MK-626 逆转。敲除 lncRNA ENSMUST00000155383 可抑制高血压小鼠 EC 中 MK-626 诱导的 Cacna1c 蛋白和 mRNA 表达增加、Ca2+ 水平升高以及 eNOS 磷酸化增强。 结论：lncRNA ENSMUST00000155383相关基因的失调可能通过影响钙通路在高血压诱发的内皮功能障碍中发挥重要作用。 MK-626 可能通过上调 lncRNA ENSMUST00000155383、提高 Ca2+ 浓度并随后恢复高血压中的 eNOS 活性来改善内皮功能障碍。
Objective: This study investigated the protective effects of dipeptidyl peptidase-4 inhibitor MK-626 on vascular endothelial function by regulating lncRNAs in hypertensive vasculature. Methods: Angiotensin Ⅱ (Ang Ⅱ)-loaded osmotic pumps were implanted in mice with or without MK-626 administration. GLP-1 levels in plasma were measured by ELISA. Aortic rings were suspended in myograph for tension measurement. Microarray was performed to analyze lncRNA and mRNA expression profiles. Protein expression and phosphorylation were examined by Western blot. The differentially expressed (DE)-genes were validated by qRT-PCR. The intracellular Ca2+ concentration was detected by laser confocal system. Results: MK-626 elevated plasma GLP-1 level, increased eNOS phosphorylation, improved endothelium-dependent relaxations, and reduced systolic blood pressure in Ang Ⅱ-induced hypertensive mice. Microarray revealed the dysregulations of 723 lncRNAs and 742 mRNAs were reversed by MK-626 in hypertensive mouse aortae. qRT-PCR validation showed that 13 DE-lncRNAs and eight dysregulated mRNAs in both hypertensive mouse aortae and mouse aortic endothelial cells (MAECs) were rescued by MK-626. Among them, four mRNAs (Cacna1C, Itgav, Itga8, and Npnt) were co-expressed with lncRNA ENSMUST00000155383. Cacna1C protein expression was reduced in the ECs but was elevated in smooth muscle cells from Ang Ⅱ-infused mice, which were both reversed by MK-626. Knockdown of lncRNA ENSMUST00000155383 suppressed the increased Cacna1c protein and mRNA expression, elevated Ca2+ level, and enhanced eNOS phosphorylation induced by MK-626 in the hypertensive mouse ECs. Conclusion: The dysregulations of lncRNA ENSMUST00000155383-associated genes might play crucial roles in hypertension-induced endothelial dysfunction through affecting calcium pathway. MK-626 might ameliorate endothelial dysfunction by upregulating lncRNA ENSMUST00000155383, enhancing Ca2+ concentration, and subsequently restoring eNOS activity in hypertension.
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小檗碱通过整体调节高血压小鼠主动脉中 lncRNA 和 mRNA 表达谱来改善血管功能障碍
影响因子：
3.7
作者：
Tan N;Zhang Y;Zhang Y;Li L;Zong Y;Han W;Liu L
通讯作者：
Liu L
DOI：
10.26355/eurrev_202003_20545
发表时间：
2020-01-01
影响因子：
3.3
作者：
An, J-H;Chen, Z-Y;Shi, F-W
通讯作者：
Shi, F-W
影响因子：
4.5
作者：
Simard, JM;Li, X
通讯作者：
Li, X
影响因子：
8.3
作者：
Gerzanich, V;Ivanova, S;Simard, JM
通讯作者：
Simard, JM
影响因子：
5.8
作者：
Diebold, Sebastian;Moellmann, Julia;Lehrke, Michael
通讯作者：
Lehrke, Michael