LncRNA-TCONS_00034812 in cell proliferation and apoptosis of pulmonary artery smooth muscle cells and its mechanism

Pulmonary hypertension is characterized by vascular remodeling involving smooth muscle cell proliferation and migration. Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent vasodilators, and the inhibition of aortic smooth muscle cell (ASMC) proliferation by NO has been documented, but less is known about the effects of CGRP. The mechanism by which overexpression of CGRP inhibits proliferation in pulmonary artery smooth muscle cells (PASMC) and ASMC following in vitro transfection by the gene coding for prepro-CGRP was investigated. Increased expression of p53 is known to stimulate p21, which inhibits G1 cyclin/cdk complexes, thereby inhibiting cell proliferation. We hypothesize that p53 and p21 are involved in the growth inhibitory effect of CGRP. In this study, CGRP was shown to inhibit ASMC and PASMC proliferation. In PASMC transfected with CGRP and exposed to a PKA inhibitor (PKAi), cell proliferation was restored. p53 and p21 expression increased in CGRP-treated cells but decreased in cells treated with CGRP and PKAi. PASMC treated with CGRP and a PKG inhibitor (PKGi) recovered from inhibition of proliferation induced by CGRP. ASMC treated with CGRP and then PKAi or PKGi recovered only when exposed to the PKAi and not PKGi. Although CGRP is thought to act through a cAMP-dependent pathway, cGMP involvement in the response to CGRP has been reported. It is concluded that p53 plays a role in CGRP-induced inhibition of cell proliferation and cAMP/PKA appears to mediate this effect in ASMC and PASMC, whereas cGMP appears to be involved in PASMC proliferation.

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Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT

Cellular & Molecular Biology Letters ◽

10.1186/s11658-020-00237-6 ◽

2020 ◽

Vol 25 (1) ◽

Author(s):

Ying Zhang ◽

Yongbin Chen ◽

Guo Chen ◽

Yingling Zhou ◽

Hua Yao ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Muscle Cells ◽

Luciferase Reporter ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

Abstract Background Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in pulmonary arterial hypertension (PAH). Serotonin (5-hydroxytryptamine, 5-HT) can induce abnormal proliferation of PASMCs. The role of miR-361-3p in serotonin-induced abnormal PASMCs proliferation remains unclear. Methods The miR-361-3p level was analyzed in plasma from PAH patients and normal controls and in human PASMCs (hPASMCs) using RT-PCR. The hPASMCs were transfected with an miR-361-3p mimic and then treated with serotonin. Untransfected hPASMCs were used as the control. Cell proliferation was evaluated using an MTS assay and 5-ethynyl-2′-deoxyuridine (EdU) staining. The cell cycle stages were evaluated using flow cytometry. The association between miR-361-3p and serotonin transporter (SERT) was determined using a luciferase reporter assay and anti-AGO2 RNA immunoprecipitation assay. The protein expression was evaluated via western blotting. Results The miR-361-3p level was lower in plasma from PAH patients than in plasma from the any of the normal control subjects. The mean pulmonary arterial pressure, pulmonary vascular resistance and pulmonary vascular resistance index were higher in PAH patients whose miR-361-3p level was lower than the median value for patients than in those whose miR-361-3p level was higher than the median. Serotonin treatment reduced miR-361-3p expression in the hPASMCs. MiR-361-3p overexpression suppressed cell proliferation, promoted apoptosis, induced G1 arrest, and decreased the phosphorylation level of ERK1/2 in serotonin-treated hPASMCs. SERT was identified as an miR-361-3p target. Its overexpression alleviated the effect of miR-361-3p overexpression on serotonin-induced hPASMC proliferation and upregulation of phosphorylated ERK1/2. Conclusions The miR-361-3p level is lower in the plasma of PAH patients. Upregulation of miR-361-3p suppresses serotonin-induced proliferation of hPASMCs by targeting SERT. Our results suggest that miR-361-3p is a potential therapeutic target in PAH.

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miR‑760 mediates hypoxia-induced proliferation and apoptosis of human pulmonary artery smooth muscle cells via targeting TLR4

International Journal of Molecular Medicine ◽

10.3892/ijmm.2018.3862 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yu‑Zhong Yang ◽

Yun‑Feng Zhang ◽

Lei Yang ◽

Jing Xu ◽

Xu‑Ming Mo ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Proliferation And Apoptosis ◽

Pulmonary Artery Smooth Muscle ◽

Human Pulmonary Artery

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miR-4632 mediates PDGF-BB-induced proliferation and antiapoptosis of human pulmonary artery smooth muscle cells via targeting cJUN

AJP Cell Physiology ◽

10.1152/ajpcell.00061.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. C380-C391 ◽

Cited By ~ 16

Author(s):

Zhengjiang Qian ◽

Yanjiao Li ◽

Jidong Chen ◽

Xiang Li ◽

Deming Gou

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Vascular Remodeling ◽

Molecular Mechanisms ◽

Muscle Cells ◽

Pulmonary Vascular Remodeling ◽

Proliferation And Apoptosis ◽

Pulmonary Artery Smooth Muscle ◽

Human Pulmonary Artery

MicroRNAs (miRNAs) can regulate the proliferative status of pulmonary artery smooth muscle cells (PASMCs), which is a core factor modulating pulmonary vascular remodeling diseases, such as atherosclerosis and pulmonary arterial hypertension (PAH). Our previous work has shown that miR-4632, a rarely reported miRNA, is significantly downregulated in platelet-derived growth factor (PDGF)-BB-stimulated human pulmonary artery smooth muscle cells (HPASMCs), yet its cell function and the underlying molecular mechanisms remain to be elucidated. Here, we find that miR-4632 is highly expressed in HPASMCs and its expression significantly decreased in response to different stimuli. Functional studies revealed that miR-4632 inhibited proliferation and promoted apoptosis of HPASMCs but had no effects on cell contraction and migration. Furthermore, the cJUN was identified as a direct target gene of miR-4632, while knockdown of cJUN was necessary for miR-4632-mediated HPASMC proliferation and apoptosis. In addition, the downregulation of miR-4632 by PDGF-BB was found to associate with histone deacetylation through the activation of PDGF receptor/phosphatidylinositol 3′-kinase/histone deacetylase 4 signaling. Finally, the expression of miR-4632 was reduced in the serum of patients with PAH. Overall, our results suggest that miR-4632 plays an important role in regulating HPASMC proliferation and apoptosis by suppression of cJUN, providing a novel therapeutic miRNA candidate for the treatment of pulmonary vascular remodeling diseases. It also implies that serum miR-4632 has the potential to serve as a circulating biomarker for PAH diagnosis.

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Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation

Cardiovascular Research ◽

10.1093/cvr/cvy250 ◽

2018 ◽

Vol 115 (3) ◽

pp. 647-657 ◽

Cited By ~ 15

Author(s):

Hongyue Zhang ◽

Ying Liu ◽

Lixin Yan ◽

Siqi Wang ◽

Min Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Noncoding Rna ◽

Muscle Cells ◽

Cell Cycle Distribution ◽

Hoxa Cluster ◽

Protein Levels ◽

Pulmonary Artery Smooth Muscle

Abstract Aims Long noncoding RNAs (lncRNAs) are involved in the regulation of vascular smooth muscle cells and cardiovascular pathology. However, the contribution of lncRNAs to pulmonary hypertension (PH) remains largely unknown. The over-proliferation of pulmonary artery smooth muscle cells (PASMCs) causes pulmonary arterial smooth muscle hypertrophy and stenosis of the pulmonary vascular lumen, resulting in PH. Here, we investigated the biological role of a novel lncRNA, Hoxa cluster antisense RNA 3 (Hoxaas3), in the regulation of cell proliferation in PH. Methods and results Hoxaas3 was up-regulated in the lung vasculature of hypoxic mice and in PASMCs under hypoxic conditions. Histone H3 Lysine 9 acetylation of Hoxaas3 promoted gene expression. Moreover, high expression of Hoxaas3 was associated with cell proliferation and modulated cell cycle distribution by up-regulating Homeobox a3 at the mRNA and protein levels. Conclusion This study defined the role and mechanism of action of Hoxaas3 in the regulation of cell proliferation in PH, which should facilitate the development of new therapeutic strategies for the treatment of this disease.

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The NFU1 G206C Mutation Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells, Promotes Proliferation and Apoptosis Resistance

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2500 ◽

2020 ◽

Author(s):

J. James ◽

M. Valuparampil Varghese ◽

M. Niihori ◽

M. Zemskova ◽

P.R. Langlais ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Apoptosis Resistance ◽

Proliferation And Apoptosis ◽

Pulmonary Artery Smooth Muscle

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Effect of miR-29b on the Proliferation and Apoptosis of Pulmonary Artery Smooth Muscle Cells by Targeting Mcl-1 and CCND2

BioMed Research International ◽

10.1155/2018/6051407 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Juan Chen ◽

Yanping Li ◽

Yun Li ◽

Lijian Xie ◽

Jianyi Wang ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Cellular Proliferation ◽

Muscle Cells ◽

Proliferation And Apoptosis ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle ◽

Key Steps

The proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) are considered to be key steps in the progression of pulmonary arterial hypertension (PAH). MicroRNAs (e.g., miR-29b) have been identified in various diseases to be critical modulators of cell growth and apoptosis by targeting Mcl-1 and CCND2. However, the role of miR-29b in PAH remains unknown. So we try to investigate the effect of miR-29b on Mcl-1 and CCND2 protein in PASMCs, analyze the effect of miR-29b on the proliferation of PASMCs, and explore the significance of miR-29b in the proliferation, apoptosis, and gene therapy of PAH. It was observed that gene chip analysis showed miR-29b expression in pulmonary artery tissue. The expression of miR-29b was significantly reduced in PAH model mice. MiR-29b inhibited the proliferation of PASMCs and promoted the apoptosis of PASMCs. Mechanically, miR-29b could inhibit the expression of Mcl-1 and CCND2 protein and silenced Mcl-1 and CCND2 could abolish the change of proliferation and apoptosis of PASMCs. These results demonstrate that miR-29b suppressed cellular proliferation and promoted apoptosis of PASMCs, possibly through the inhibition of Mcl-1 and CCND2. Therefore, miR-29b may serve as a useful therapeutic tool to treat PAH.

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