Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.

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miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00344.2011 ◽

2012 ◽

Vol 303 (8) ◽

pp. L682-L691 ◽

Cited By ~ 86

Author(s):

Deming Gou ◽

Ramaswamy Ramchandran ◽

Xiao Peng ◽

Lijun Yao ◽

Kang Kang ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Hypoxia Inducible Factor ◽

Cell Number ◽

Regulation Of Transcription ◽

Pulmonary Artery Smooth Muscle

MicroRNAs (miRNAs) were recently reported to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH), but it is not clear which miRNAs are important or what pathways are involved in the process. Because hypoxia is an important stimulus for human pulmonary artery smooth muscle cell (HPASMC) proliferation and PAH, we performed miRNA microarray assays in hypoxia-treated and control HPASMC. We found that miR-210 is the predominant miRNA induced by hypoxia in HPASMC. Induction of miR-210 was also observed in whole lungs of mice with chronic hypoxia-induced PAH. We found that transcriptional induction of miR-210 in HPASMC is hypoxia-inducible factor-1α dependent. Inhibition of miR-210 in HPASMC caused a significant decrease in cell number due to increased apoptosis. We found that miR-210 appears to mediate its antiapoptotic effects via the regulation of transcription factor E2F3, a direct target of miR-210. Our results have identified miR-210 as a hypoxia-inducible miRNA both in vitro and in vivo, which inhibits pulmonary vascular smooth muscle cell apoptosis in hypoxia by specifically repressing E2F3 expression.

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The Anti-Osteoprotegerin (OPG) Antibody Ky3 Attenuates OPG-Fas Mediated Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Pro-Inflammatory Signalling In Vitro and In Vivo

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2679 ◽

2020 ◽

Author(s):

A. Lawrie ◽

N.D. Arnold ◽

J.A. Pickworth ◽

L.E. West ◽

J. Papworth ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Smooth Muscle Cell Proliferation ◽

Pulmonary Artery Smooth Muscle ◽

Inflammatory Signalling

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Faculty Opinions recommendation of Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12312957.13487055 ◽

2011 ◽

Author(s):

Paul Corris

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cell ◽

Lung Disease ◽

Muscle Cell ◽

Chronic Lung Disease ◽

Cell Senescence ◽

Pathogenic Mechanism ◽

Pulmonary Artery Smooth Muscle

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Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000480218 ◽

2017 ◽

Vol 42 (6) ◽

pp. 2569-2581 ◽

Cited By ~ 47

Author(s):

Zengxian Sun ◽

Xiaowei Nie ◽

Shuyang Sun ◽

Shumin Dong ◽

Chunluan Yuan ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Remodeling ◽

Pulmonary Artery Smooth Muscle ◽

And Migration ◽

Proliferation And Migration

Background/Aims: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA–maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. Methods: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. Results: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3–induced smooth muscle cell proliferation. Conclusions: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

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