DNA methylation signatures of pulmonary arterial smooth muscle cells in chronic thromboembolic pulmonary hypertension

2018 ◽  
Vol 50 (5) ◽  
pp. 313-322 ◽  
Author(s):  
Ying Wang ◽  
Xiaoxi Huang ◽  
Dong Leng ◽  
Jifeng Li ◽  
Lei Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening disease, which is often underpinned by vascular remodeling. Pulmonary arterial smooth muscle cells (PASMCs) are the main participants in vascular remodeling. However, their biological role in CTEPH is not entirely clear. In the present study, we analyzed the whole epigenome-wide DNA methylation profile of cultured PASMCs from CTEPH and control cell lines with the Illumina Human Methylation 450K BeadChip. A total of 6,829 significantly differentially methylated probes (DMPs) were detected between these two groups. Among these, 4,246 DMPs were hypermethylated, while 2,583 DMPs were hypomethylated. The functional enrichment analysis of 1,743 DMPs in the promoter regions and corresponding genes indicated that DNA hypermethylation and hypomethylation might be involved in the regulation of genes that have multifarious biological roles, including roles in cancer-related diseases, the regulation of the actin cytoskeleton, cell adhesion, and pattern specification processes. The observed methylations were categorized into the most important functions, including those involved in cell proliferation, immunity, and migration. We speculate that these methylations were most likely involved in the possible pathophysiology of CTEPH. Gene interaction analysis pertaining to signal networks confirmed that PIK3CA and PIK3R1 were important mediators in these whole networks. The mRNA levels of PIK3CA, HIC1, and SSH1 were verified by qPCR and corresponded with DNA methylation differences. Understanding epigenetic features associated with CTEPH may provide new insights into the mechanism that underlie this condition.

PDGF/MEK/ERK axis represses Ca2+ clearance via decreasing the abundance of plasma membrane Ca2+ pump PMCA4 in pulmonary arterial smooth muscle cells

2021 ◽  
Vol 320 (1) ◽  
pp. C66-C79
Author(s):  
Liyu Deng ◽  
Jidong Chen ◽  
Ting Wang ◽  
Bin Chen ◽  
Lei Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by vascular remodeling and vasoconstriction, which is associated with increased intracellular calcium ion concentration ([Ca2+]i). Platelet-derived growth factor-BB (PDGF-BB) is the most potent mitogen for pulmonary arterial smooth muscle cells (PASMCs) and is involved in vascular remodeling during PAH development. PDGF signaling has been proved to participate in maintaining Ca2+ homeostasis of PASMCs; however, the mechanism needs to be further elucidated. Here, we illuminate that the expression of plasma membrane calcium-transporting ATPase 4 (PMCA4) was downregulated in PASMCs after PDGF-BB stimulation, which could be abolished by restraining the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK). Functionally, suppression of PMCA4 attenuated the [Ca2+]i clearance in PASMCs after Ca2+ entry, promoting cell proliferation and elevating cell locomotion through mediating formation of focal adhesion. Additionally, the expression of PMCA4 was decreased in the pulmonary artery of monocrotaline (MCT)- or hypoxia-induced PAH rats. Moreover, knockdown of PMCA4 could increase the right ventricular systolic pressure (RVSP) and wall thickness (WT) of pulmonary artery in rats raised under normal conditions. Taken together, our findings demonstrate the importance of the PDGF/MEK/ERK/PMCA4 axis in intracellular Ca2+ homeostasis in PASMCs, indicating a functional role of PMCA4 in pulmonary arterial remodeling and PAH development.

scholarly journals Circular RNA Calm4 Regulates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cells Pyroptosis via the Circ-Calm4/miR-124-3p/PDCD6 Axis

2021 ◽  
Author(s):  
Yuan Jiang ◽  
Huiyu Liu ◽  
Hang Yu ◽  
Yang Zhou ◽  
Junting Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Circular Rna ◽  
Circular Rnas ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Objective: Circular RNAs are emerging as important regulators of pulmonary hypertension where pyroptosis plays a critical role. However, whether and how the circular RNAs regulate pyroptosis remained unexplored. Here, we show evidence for the involvement of a specific circular RNA known as circ-Calm4 in pulmonary hypertension and the underlying signaling pathway in pyroptosis. Approach and Results: Circ-Calm4 was upregulated in both mouse model of pulmonary hypertension in vivo and cultured smooth muscle cells in vitro. We performed immunoblotting, quantitative real-time PCR, LDH (lactate dehydrogenase) release assay, Annexin V-FITC/propidium iodide double staining, Hoechst 33342/propidium iodide fluorescence staining, and immunostaining to clarify the roles of circ-Calm4 in pulmonary arterial smooth muscle cell pyroptosis. Silencing the circ-Calm4 with its small-interfering RNA mitigated the upregulation of pyroptosis related phenotypes induced by hypoxia. Luciferase reporter assays confirmed that miR-124-3p suppressed the luciferase activity of the circ-Calm4 and RNA fluorescence in situ hybridization showed the colocalization of circ-Calm4 and miR-124-3p. The circ-Calm4 was found to act as a competitive endogenous RNA to regulate miR-124-3p. The pyroptosis-related alterations were all diminished with miR-124-3p in hypoxic pulmonary arterial smooth muscle cells. Inhibition of the gene targeted by miR-124-3p encoding the Pdcd6 (programmed cell death protein 6) abrogated pyroptosis-related phenotypes under hypoxia stimulation. Conclusions: Our findings show a new signaling pathway, the circ-Calm4/miR-124-3p/ Pdcd6 axis was demonstrated in regulation of hypoxia-induced pyroptosis, which may potentially be useful for the design of therapeutic strategies for protecting the cellular functionality against pyroptosis as well as pulmonary hypertension.

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