Berberine ameliorates vascular dysfunction by a global modulation of lncRNA and mRNA expression profiles in hypertensive mouse aortae.
Berberine ameliorates vascular dysfunction by a global modulation of lncRNA and mRNA expression profiles in hypertensive mouse aortae.
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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
DOI：
10.1371/journal.pone.0247621
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Tan N;Zhang Y;Zhang Y;Li L;Zong Y;Han W;Liu L
目的探讨黄连素对高血压血管的治疗作用机制。方法将血管紧张素II（Ang II）渗透泵植入C57 BL/6J小鼠体内，并给予或不给予小檗碱。将小鼠后肢悬挂在肌电描记器中进行力测量。利用基因芯片技术分析了大肠杆菌中lncRNA和mRNA的表达谱。然后通过qRT-PCR验证这些失调的表达。构建LncRNA-mRNA共表达网络，揭示其特异性关系。结果Ang Ⅱ可引起小鼠血压升高，黄连素可抑制Ang Ⅱ引起的血压升高。高血压小鼠受损的内皮依赖性主动脉舒张功能得到恢复。微阵列数据显示，Ang Ⅱ上调了578条lncRNA和554条mRNA，下调了320条lncRNA和377条mRNA，黄连素处理后两者均被逆转。差异表达基因（14个lncRNA和6个mRNAs）的qRT-PCR验证结果与微阵列数据完全一致。GO分析表明，这些验证的差异表达基因在"细胞过程"、"生物学调节"和"生物学过程的调节"方面显著富集，而KEGG分析鉴定了血管功能相关的通路，包括cAMP信号通路、cGMP-PKG信号通路和钙信号通路等。ENSMUST00000155383和AK041185主要在内皮细胞中表达。结论ENSMUST00000144849、NR_028422、ENSMUST00000155383、AK041185和uc.335 + 5个lncRNA可能通过靶向关键mRNA并随后影响血管功能相关通路而在高血压血管中发挥关键调节作用。这些lncRNA受小檗碱的调控，为小檗碱治疗高血压提供了新的潜在靶点。此外，lncRNA ENSMUST00000144849、ENSMUST00000155383和AK041185可能参与血管内皮细胞功能的保护。
Objective The current study investigated the mechanism underlying the therapeutic effects of berberine in the vasculature in hypertension. Methods Angiotensin II (Ang II)-loaded osmotic pumps were implanted in C57BL/6J mice with or without berberine administration. Mouse aortae were suspended in myograph for force measurement. Microarray technology were performed to analyze expression profiles of lncRNAs and mRNAs in the aortae. These dysregulated expressions were then validated by qRT-PCR. LncRNA-mRNA co-expression network was constructed to reveal the specific relationships. Results Ang Ⅱ resulted in a significant increase in the blood pressure of mice, which was suppressed by berberine. The impaired endothelium-dependent aortic relaxation was restored in hypertensive mice. Microarray data revealed that 578 lncRNAs and 554 mRNAs were up-regulated, while 320 lncRNAs and 377 mRNAs were down-regulated in the aortae by Ang Ⅱ; both were reversed by berberine treatment. qRT-PCR validation results of differentially expressed genes (14 lncRNAs and 6 mRNAs) were completely consistent with the microarray data. GO analysis showed that these verified differentially expressed genes were significantly enriched in terms of “cellular process”, “biological regulation” and “regulation of biological process”, whilst KEGG analysis identified vascular function-related pathways including cAMP signaling pathway, cGMP-PKG signaling pathway, and calcium signaling pathway etc. Importantly, we observed that lncRNA ENSMUST00000144849, ENSMUST00000155383, and AK041185 were majorly expressed in endothelial cells. Conclusion The present results suggest that the five lncRNAs ENSMUST00000144849, NR_028422, ENSMUST00000155383, AK041185, and uc.335+ might serve critical regulatory roles in hypertensive vasculature by targeting pivotal mRNAs and subsequently affecting vascular function-related pathways. Moreover, these lncRNAs were modulated by berberine, therefore providing the novel potential therapeutic targets of berberine in hypertension. Furthermore, lncRNA ENSMUST00000144849, ENSMUST00000155383, and AK041185 might be involved in the preservation of vascular endothelial cell function.
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