TMEM16A Regulates Pulmonary Arterial Smooth Muscle Cells Proliferation via p38MAPK/ERK Pathway in High Pulmonary Blood Flow-Induced Pulmonary Arterial Hypertension

2020 ◽  
Vol 58 (1) ◽  
pp. 27-37
Author(s):  
Dongli Liu ◽  
Kai Wang ◽  
Danyan Su ◽  
Yanyun Huang ◽  
Lifeng Shang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Pulmonary Blood Flow ◽  
Pulmonary Arteries ◽  
Erk Signaling ◽  
Shunt Group ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

<b><i>Objective:</i></b> Pulmonary arterial hypertension (PAH) is a complex disease of the small pulmonary arteries that is mainly characterized by vascular remodeling. It has been demonstrated that excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a pivotal role in vascular remodeling during PAH. The present study was undertaken to explore the role of TMEM16A in regulating PASMCs proliferation in high pulmonary blood flow-induced PAH. <b><i>Methods:</i></b> Aortocaval shunt surgery was undertaken to establish an animal model. Pulmonary artery pressure and pulmonary vascular structure remodeling (PVSR) were tested. Immunohistochemical staining and Western blot were performed to investigate the expression of TMEM16A. The proliferation of PASMCs was tested by the MTT assay. After treating PASMCs with TMEM16A-siRNA, the expression of proliferating cell nuclear antigen (PCNA), phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), and phosphorylated extracellular signal-regulated kinase (p-ERK) signaling in PASMCs were tested. <b><i>Results:</i></b> PAH and PVSR developed 11 weeks postoperation. Elevated expression of TMEM16A accompanied by high expression of PCNA in pulmonary arteries of the shunt group was observed. The increased proliferation of PASMCs and increased expression of TMEM16A and PCNA, along with activated p-p38MAPK and p-ERK signaling in PASMCs of the shunt group, were all attenuated by siRNA-specific TMEM16A knockdown. <b><i>Conclusion:</i></b> TMEM16A regulates PASMCs proliferation in high pulmonary blood flow-induced PAH, and the p38MAPK/ERK signaling pathway is probably involved.

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.

eNOS expression is not altered in pulmonary vascular remodeling due to increased pulmonary blood flow

1998 ◽  
Vol 274 (6) ◽  
pp. L1058-L1065 ◽  
Author(s):  
Allen D. Everett ◽  
Timothy D. Le Cras ◽  
Chun Xue ◽  
Roger A. Johns
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Pulmonary Blood Flow ◽  
Nuclear Antigen ◽  
Mrna Levels ◽  
Altered Expression ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Congenital heart lesions resulting in increased pulmonary blood flow are common and if unrepaired often lead to pulmonary hypertension and heart failure. Therefore, we hypothesized that increased pulmonary blood flow without changes in pressure would result in remodeling of the pulmonary arterial wall. Furthermore, because the vasodilator nitric oxide is produced by the lung, is regulated by flow in the systemic circulation, and has been associated with the regulation of smooth muscle cell proliferation, we hypothesized that increased pulmonary blood flow would result in altered expression of endothelial nitric oxide synthase (eNOS). To study this hypothesis, 42-day-old Sprague-Dawley rats had creation of an aortocaval shunt to increase pulmonary blood flow for 6 wk. The shunt resulted in a significant increase in the heart- and lung-to-body weight ratios (>2-fold; P < 0.05) without significant alteration of pulmonary or systemic blood pressures. Significant thickening of the pulmonary arterial medial wall developed, with increased muscularization of small (50–100 μm)- and medium (101–200 μm)-sized arteries as evidenced by α-actin smooth muscle staining. Proliferating cell nuclear antigen staining and bromodeoxyuridine labeling did not detect proliferating smooth muscle cells in the vascular wall. eNOS Western and Northern blot analyses and immunohistochemical staining demonstrated that eNOS protein and mRNA levels were not altered in the shunt lungs compared with sham controls. Therefore, increased pulmonary flow without increased pressure resulted in pulmonary artery medial thickening, without ongoing proliferation. Unlike chronic hypoxia-induced vascular remodeling, the pulmonary vascular remodeling resulting from increased pulmonary blood flow is not associated with changes in eNOS.

scholarly journals Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype

2015 ◽  
Vol 308 (8) ◽  
pp. C581-C593 ◽  
Author(s):  
Ruby A. Fernandez ◽  
Jun Wan ◽  
Shanshan Song ◽  
Kimberly A. Smith ◽  
Yali Gu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Pulmonary Vascular Remodeling ◽  
Contractile Phenotype ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle ◽  
Phenotypic Transition

Pulmonary arterial hypertension (PAH) is a progressive disease that, if left untreated, eventually leads to right heart failure and death. Elevated pulmonary arterial pressure (PAP) in patients with PAH is mainly caused by an increase in pulmonary vascular resistance (PVR). Sustained vasoconstriction and excessive pulmonary vascular remodeling are two major causes for elevated PVR in patients with PAH. Excessive pulmonary vascular remodeling is mediated by increased proliferation of pulmonary arterial smooth muscle cells (PASMC) due to PASMC dedifferentiation from a contractile or quiescent phenotype to a proliferative or synthetic phenotype. Increased cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC is a key stimulus for cell proliferation and this phenotypic transition. Voltage-dependent Ca2+ entry (VDCE) and store-operated Ca2+ entry (SOCE) are important mechanisms for controlling [Ca2+]cyt. Stromal interacting molecule proteins (e.g., STIM2) and Orai2 both contribute to SOCE and we have previously shown that STIM2 and Orai2, specifically, are upregulated in PASMC from patients with idiopathic PAH and from animals with experimental pulmonary hypertension in comparison to normal controls. In this study, we show that STIM2 and Orai2 are upregulated in proliferating PASMC compared with contractile phenotype of PASMC. Additionally, a switch in Ca2+ regulation is observed in correlation with a phenotypic transition from contractile PASMC to proliferative PASMC. PASMC in a contractile phenotype or state have increased VDCE, while in the proliferative phenotype or state PASMC have increased SOCE. The data from this study indicate that upregulation of STIM2 and Orai2 is involved in the phenotypic transition of PASMC from a contractile state to a proliferative state; the enhanced SOCE due to upregulation of STIM2 and Orai2 plays an important role in PASMC proliferation.

Staurosporine aglycone bilaterally regulates ERK1/2 phosphorylation in rat pulmonary arterial smooth muscle cells

2008 ◽  
Vol 86 (7) ◽  
pp. 424-430
Author(s):  
Jianing Zhang ◽  
Xiaobo Tang ◽  
Changlian Lu ◽  
Lei Guo ◽  
Shuang Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Pulmonary Arteries ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle ◽  
Staurosporine Aglycone

Staurosporine, a protein kinase C (PKC) inhibitor, has been reported to regulate the phosphorylation of ERK1/2 in several cell lines. It is still unknown, however, whether its derivative staurosporine aglycone (SA) has the same effect on ERK1/2 activation. In this study, we investigated the effect of SA on ERK1/2 activity in rat pulmonary arteries and pulmonary arterial smooth muscle cells (PASMCs). The pulmonary arteries and PASMCs were treated with SA at different time points and concentrations, and the activation of ERK1/2 was analyzed by Western blotting. The results showed that SA at nanomolar concentrations suppressed ERK1/2 phosphorylation through the PKC pathway alone, but SA at 30 µmol/L for 2 h enhanced the phosphorylation of ERK1/2. The activation of ERK1/2 was inhibited by the MAPK/ERK kinase inhibitor PD98059 or the protein kinase A (PKA) activator isoproterenol. Together, these results suggest that SA has a strong dual regulating effect on ERK1/2 through the PKC and (or) PKA pathways in rat PASMCs.

scholarly journals Icotinib Attenuates Monocrotaline-Induced Pulmonary Hypertension by Preventing Pulmonary Arterial Smooth Muscle Cell Dysfunction

2020 ◽  
Vol 33 (8) ◽  
pp. 775-783
Author(s):  
Li-Yao Peng ◽  
Min Yu ◽  
Ming-Xia Yang ◽  
Ping Liu ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Signaling Pathway ◽  
Vascular Remodeling ◽  
Erk Signaling ◽  
Phenotypic Switching ◽  
Pulmonary Vascular Remodeling ◽  
Epidermal Growth ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Abstract Background Aberrant activation of epidermal growth factor receptor (EGFR) signaling pathway is associated with the pathogenesis of pulmonary hypertension (PH). However, the effect of icotinib, a first generation of EGFR tyrosine kinase inhibitor (EGFR-TKI), on PH remains to be elucidated. Methods PH rat model was established by a single intraperitoneal injection of monocrotaline (MCT, 60 mg/kg). Icotinib (15, 30, and 60 mg/kg/day) was administered by oral gavage from the day of MCT injection. After 4 weeks, hemodynamic parameters and histological changes of the pulmonary arterial vessels were assessed, and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) was determined in vivo. Moreover, the effects of icotinib (10 µM) on epidermal growth factor (EGF, 50 ng/ml)-stimulated proliferation, migration, and phenotypic switching of human PASMCs were explored in vitro. Results Icotinib significantly reduced the right ventricular systolic pressure and right ventricle hypertrophy index in rats with MCT-induced PH. Moreover, icotinib improved MCT-induced pulmonary vascular remodeling. The expression of contractile marker (smooth muscle 22 alpha (SM22α)) and synthetic markers (osteopontin (OPN) and vimentin) in pulmonary artery was restored by icotinib treatment. In vitro, icotinib suppressed EGF-induced PASMCs proliferation and migration. Meanwhile, icotinib inhibited EGF-induced downregulation of α-smooth muscle actin and SM22α and upregulation of OPN and Collagen I in PASMCs, suggesting that icotinib could inhibit EGF-induced phenotypic switching of PASMCs. Mechanistically, these effects of icotinib were associated with the inhibition of EGFR-Akt/ERK signaling pathway. Conclusions Icotinib can attenuate MCT-induced pulmonary vascular remodeling and improve PH. This effect of icotinib might be attributed to preventing PASMC dysfunction by inhibiting EGFR-Akt/ERK signaling pathway.

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.

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