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

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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A Single Mutation in NFU1 Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells and Drives Proliferation with Apoptosis Resistance

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2019.10.303 ◽

2019 ◽

Vol 145 ◽

pp. S113-S114

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Single Mutation ◽

Apoptosis Resistance ◽

Pulmonary Artery Smooth Muscle

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Exosomes Derived from Human Pulmonary Artery Endothelial Cells Shift the Balance between Proliferation and Apoptosis of Smooth Muscle Cells

Cardiology ◽

10.1159/000453544 ◽

2017 ◽

Vol 137 (1) ◽

pp. 43-53 ◽

Cited By ~ 30

Author(s):

Lin Zhao ◽

Hui Luo ◽

Xiaohui Li ◽

Tangzhiming Li ◽

Jingni He ◽

...

Keyword(s):

Endothelial Cells ◽

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Apoptosis Resistance ◽

Proliferation And Apoptosis ◽

Pulmonary Arterial ◽

Human Pulmonary Artery

Background: The overproliferation of pulmonary vascular cells is noted in pulmonary hypertension. The role of exosomes from pulmonary artery endothelial cells (PAEC) in the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMC) remains unclear. Methods: Exosomes were isolated and purified from the culture medium of PAEC using a commercial kit. Lipopolysaccharide (LPS), hypoxia, and hydrogen peroxide were utilized to induce PAEC injury. Coculture of PAEC and PASMC was conducted using Transwell plates, and GW4869 was applied to inhibit exosome release. The proliferation and apoptosis level of PASMC was assayed by MTT assay, apoptosis staining, and cleaved caspase-3 immunoblotting. Plasma exosomes were isolated by differential ultracentrifugation. Results: LPS or hypoxia enhance exosome release from PAEC. Release of PAEC-derived exosomes positively correlates with LPS concentration. The coculture of LPS-disposed PAEC with PASMC leads to overproliferation and apoptosis resistance in PASMC, and the exosome inhibitor GW4869 can partly cancel out this effect. Exosomes derived from PAEC could be internalized into PASMC, and thus promote proliferation and induce apoptosis resistance in PASMC. Idiopathic pulmonary arterial hypertension patients exhibit a higher circulation level of endothelium-derived exosomes. Conclusions: Inflammation and hypoxia could induce PAEC to release exosomes. PAEC- derived exosomes are involved in overproliferation and apoptosis resistance in PASMC, by which they may contribute to the pathogenesis of pulmonary hypertension.

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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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Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway

PeerJ ◽

10.7717/peerj.9110 ◽

2020 ◽

Vol 8 ◽

pp. e9110

Author(s):

Suiqing Huang ◽

Yuan Yue ◽

Kangni Feng ◽

Xiaolin Huang ◽

Huayang Li ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Conditioned Medium ◽

Muscle Cells ◽

Cell Counting ◽

Apoptosis Resistance ◽

Caspase 9 ◽

Pulmonary Artery Smooth Muscle ◽

Apoptotic Proteins

Background Immunity and inflammation are considered to be central features of pulmonary artery hypertension (PAH), in which macrophages are one of the main components of inflammatory cell infiltration around the pulmonary artery. M2b macrophages, which are different from M1 and M2 macrophages, are believed to have immunomodulatory activities and produce little fibrosis. The purpose of this study was to explore the effect of M2b macrophages on pulmonary artery smooth muscle cells (PASMCs) derived from monocrotaline-induced PAH rats. Methods PASMCs were cultured in serum-free medium, the supernatant of M0 macrophages, or the supernatant of M2b macrophages for 24 hours. Then cell proliferation was assessed by cell counting kit-8 and cell migration ability was detected by wound healing and transwell assays. The apoptosis rate of cells was determined by TUNEL staining and annexin V-PE/7-ADD staining. Western blot was used to detect the expression of Bcl-2 family proteins, cleaved caspase-9 and PI3K/Akt/FoxO3a pathway. LY294002 (a specific inhibitor of PI3K) was used to investigate its effect on PASMCs and its relationship with M2b macrophages. Results Conditioned medium from M2b macrophages significantly inhibited the proliferation and migration of PASMCs compared with the control group and M0 macrophage group. Furthermore, conditioned medium from M2b macrophages promote PASMC apoptosis and increased the expression of pro-apoptotic proteins Bax and cleaved caspase-9, inhibited the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. Finally, conditioned medium from M2b macrophages inhibited the PI3K/Akt/FoxO3a pathway. Inhibition of PI3K/Akt/FoxO3a pathway also significantly inhibit the proliferation, migration, and apoptosis resistance of PASMCs. Conclusion Conditioned medium from M2b macrophages can inhibit the proliferation, migration, and apoptosis resistance of PASMCs, which may be at least partially by deregulating the PI3K/Akt/FoxO3a pathway.

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