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

Tan, Na; Zhang, Yi; Zhang, Yan; Li, Li; Zong, Yi; Han, Wenwen; Liu, Limei

doi:10.1371/journal.pone.0247621

Cited by 6 publications

(3 citation statements)

References 41 publications

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“…Numerous studies have verified that vascular endothelial cell dysfunction and lncRNA activity may together be associated with hypertension ( Lorenzen and Thum, 2016 ; Konukoglu and Uzun, 2017 ). The levels of five lncRNAs were found to be modulated by the administration of 100 mg/kg berberine in mice with hypertention, which may preserve vascular endothelial cell function ( Tan et al, 2021 ). Endothelial microparticles (EMPs) are extracellular vesicles that are shed by the endothelium as a result of activation, injury, or apoptosis of endothelial cells, and are considered important biomarkers of the status of endothelial cells and vascular function ( Sun et al, 2016 ).…”

Section: Effects Of Berberine On Vascular Diseasesmentioning

confidence: 99%

Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases

Peng

et al. 2021

Front. Pharmacol.

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Traditional Chinese medicine plays a significant role in the treatment of various diseases and has attracted increasing attention for clinical applications. Vascular diseases affecting vasculature in the heart, cerebrovascular disease, atherosclerosis, and diabetic complications have compromised quality of life for affected individuals and increase the burden on health care services. Berberine, a naturally occurring isoquinoline alkaloid form Rhizoma coptidis, is widely used in China as a folk medicine for its antibacterial and anti-inflammatory properties. Promisingly, an increasing number of studies have identified several cellular and molecular targets for berberine, indicating its potential as an alternative therapeutic strategy for vascular diseases, as well as providing novel evidence that supports the therapeutic potential of berberine to combat vascular diseases. The purpose of this review is to comprehensively and systematically describe the evidence for berberine as a therapeutic agent in vascular diseases, including its pharmacological effects, molecular mechanisms, and pharmacokinetics. According to data published so far, berberine shows remarkable anti-inflammatory, antioxidant, antiapoptotic, and antiautophagic activity via the regulation of multiple signaling pathways, including AMP-activated protein kinase (AMPK), nuclear factor κB (NF-κB), mitogen-activated protein kinase silent information regulator 1 (SIRT-1), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), janus kinase 2 (JAK-2), Ca2+ channels, and endoplasmic reticulum stress. Moreover, we discuss the existing limitations of berberine in the treatment of vascular diseases, and give corresponding measures. In addition, we propose some research perspectives and challenges, and provide a solid evidence base from which further studies can excavate novel effective drugs from Chinese medicine monomers.

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Section: Effects Of Berberine On Vascular Diseasesmentioning

confidence: 99%

Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases

Peng

et al. 2021

Front. Pharmacol.

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“…Importantly, lncRNA ENSMUST00000155383, which was included in the 13 DE-lncRNAs we have identified, was coexpressed with Cacna1C, Itgav, Itga8, and Npnt. Also, our previous study revealed that lncRNA ENSMUST00000155383 mainly expressed in endothelial cells of the vasculature, which was downregulated in hypertensive mouse aortae (Tan et al, 2021). Altogether, we speculated the dysregulation of lncRNA ENSMUST00000155383 and the four related-mRNAs might play an important role in vascular endothelial dysfunction under hypertension.…”

Section: Discussionmentioning

confidence: 71%

LncRNA ENSMUST00000155383 is Involved in the Improvement of DPP-4 Inhibitor MK-626 on Vascular Endothelial Function by Modulating Cacna1c-Mediated Ca2+ Influx in Hypertensive Mice

Zeng

Tan

Zong

et al. 2021

Front. Mol. Biosci.

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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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“…Surprisingly, while transcriptomic profiles of AngII-treated organs/tissues are available in the kidneys ( 18 ), heart ( 19 ), or abdominal aortic aneurysm in ApoE-/- mice ( 20 ), the AngII treatment protocol varies widely between studies, and transcriptomic data on the arterial tissue of WT mice were rarely reported ( 21 – 23 ), with no attempt to analyze any legacy effect.…”

Section: Introductionmentioning

confidence: 99%

Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”

Pothen

Verdoy

Mulder

et al. 2022

Front. Cardiovasc. Med.

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BackgroundActivation of the renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of hypertension. Published evidence on a putative “memory effect” of AngII on the vascular components is however scarce.AimTo evaluate the long-term effects of transient exposure to AngII on the mouse heart and the arterial tissue.MethodsBlood pressure, cardiovascular tissue damage and remodeling, and systemic oxidative stress were evaluated in C57/B6/J mice at the end of a 2-week AngII infusion (AngII); 2 and 3 weeks after the interruption of a 2-week AngII treatment (AngII+2W and AngII +3W; so-called “memory” conditions) and control littermate (CTRL). RNAseq profiling of aortic tissues was used to identify potential key regulated genes accounting for legacy effects on the vascular phenotype. RNAseq results were validated by RT-qPCR and immunohistochemistry in a reproduction cohort of mice. Key findings were reproduced in a homotypic cell culture model.ResultsThe 2 weeks AngII infusion induced cardiac hypertrophy and aortic damage that persisted beyond AngII interruption and despite blood pressure normalization, with a sustained vascular expression of ICAM1, infiltration by CD45+ cells, and cell proliferation associated with systemic oxidative stress. RNAseq profiling in aortic tissue identified robust Acta2 downregulation at transcript and protein levels (α-smooth muscle actin) that was maintained beyond interruption of AngII treatment. Among regulators of Acta2 expression, the transcription factor Myocardin (Myocd), exhibited a similar expression pattern. The sustained downregulation of Acta2 and Myocd was associated with an increase in H3K27me3 in nuclei of aortic sections from mice in the “memory” conditions. A sustained downregulation of ACTA2 and MYOCD was reproduced in the cultured human aortic vascular smooth muscle cells upon transient exposure to Ang II.ConclusionA transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting supporting a “memory” effect despite stimulus withdrawal.

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

Cited by 6 publications

References 41 publications

Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases

Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases

LncRNA ENSMUST00000155383 is Involved in the Improvement of DPP-4 Inhibitor MK-626 on Vascular Endothelial Function by Modulating Cacna1c-Mediated Ca2+ Influx in Hypertensive Mice

Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”

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