Dataset Information

Berberine ameliorates vascular dysfunction by a global modulation of lncRNA and mRNA expression profiles in hypertensive mouse aortae.

ABSTRACT:

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 ? 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 ?; 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.

SUBMITTER: Tan N

PROVIDER: S-EPMC7901729 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Berberine ameliorates vascular dysfunction by a global modulation of lncRNA and mRNA expression profiles in hypertensive mouse aortae.

Tan Na N Zhang Yi Y Zhang Yan Y Li Li L Zong Yi Y Han Wenwen W Liu Limei L

PloS one 20210223 2

<h4>Objective</h4>The current study investigated the mechanism underlying the therapeutic effects of berberine in the vasculature in hypertension.<h4>Methods</h4>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 b ...[more]

PMID: 33621262

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Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.

Dataset Information

Berberine ameliorates vascular dysfunction by a global modulation of lncRNA and mRNA expression profiles in hypertensive mouse aortae.

Objective

Methods

Results

Conclusion

Publications

Berberine ameliorates vascular dysfunction by a global modulation of lncRNA and mRNA expression profiles in hypertensive mouse aortae.

Similar Datasets

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