Identification of a Novel Gene Correlated With Vascular Smooth Muscle Cells Proliferation and Migration in Chronic Thromboembolic Pulmonary Hypertension

Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of the proximal pulmonary arteries, which result in vascular remodeling of the distal pulmonary artery. While the cellular and molecular mechanisms underlying CTEPH pathogenesis remain incompletely understood, recent evidence implicates vascular remodeling. Here, we identify the molecular mechanisms that contribute to vascular remodeling in CTEPH.Methods: Microarray data (GSE130391) for patients with CTEPH and healthy controls were downloaded from the Gene Expression Omnibus (GEO) and screened for differentially expressed genes (DEGs). DEGs were functionally annotated using Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A protein–protein interaction (PPI) network was constructed to identify hub genes. Finally, pulmonary artery samples were harvested from patients with CTEPH (n = 10) and from controls (n = 10) and primary vascular smooth muscle cells (VSMCs) were cultured. Effects of the proto-oncogene FOS on VSMC proliferation and migration were assessed using expression and knockdown studies.Results: We detected a total of 292 DEGs, including 151 upregulated and 141 downregulated genes. GO analysis revealed enrichment of DEGs in biological processes of signal transduction, response to lipopolysaccharide, signal transduction, and myeloid dendritic cell differentiation. Molecular function analysis revealed enrichment in tumor necrosis factor (TNF)-activated receptor activity, transcriptional activator activity, and protein homodimerization activity. The expression of TNF-α and its receptor (sTNFR1 and sTNFR2) were significantly higher in CTEPH group, compared with control group. KEGG pathway analysis revealed enrichment in salmonella infection, pathways in cancer, osteoclast differentiation, and cytokine-cytokine receptor interaction. Hub genes in the PPI included FOS, suggesting an important role for this gene in vascular remodeling in CTEPH. Primary VSMCs derived from patients with CTEPH showed increased FOS expression and high proliferation and migration, which was attenuated by FOS inhibition. In control VSMCs, TNF-α treatment increased proliferation and migration, which FOS inhibition likewise attenuated.Conclusion: TNF-α drives CTEPH pathogenesis by promoting VSMC proliferation and migration via increased FOS expression. These results advance our understanding of the molecular mechanisms of vascular remodeling in CTEPH, and may inform the development of new therapeutic targets.

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Corylin Inhibits Vascular Cell Inflammation, Proliferation and Migration and Reduces Atherosclerosis in ApoE-Deficient Mice

Antioxidants ◽

10.3390/antiox9040275 ◽

2020 ◽

Vol 9 (4) ◽

pp. 275

Author(s):

Chin-Chuan Chen ◽

Hung-Yuan Li ◽

Yann-Lii Leu ◽

Yu-Ju Chen ◽

Chia-Jen Wang ◽

...

Keyword(s):

Flavonoid Compound ◽

Ros Production ◽

Monocyte Adhesion ◽

Vascular Cell ◽

Vsmc Proliferation ◽

Tnf Α ◽

Anti Inflammatory ◽

And Migration ◽

Deficient Mice ◽

Proliferation And Migration

Atherosclerosis is a complex disease that includes several events, including reactive oxygen species (ROS) stress, inflammation, endothelial dysfunction, lipid deposition, and vascular smooth muscle cell (VSMC) proliferation and migration, which result in atherosclerotic plaque formation. Corylin, a flavonoid compound, is known to exhibit antioxidative, anti-inflammatory and antiproliferative effects. However, it remains unknown whether corylin could modulate atherogenesis. Here, we identified the anti-inflammatory effect of corylin in tumor necrosis factor-α (TNF-α)-induced vascular cells. In human umbilical vein endothelial cells (HUVECs), corylin suppressed TNF-α-induced monocyte adhesion to the HUVECs and transmigration by downregulating the ROS/JNK/nuclear factor-kappa beta (NF-κB) p65 pathway. In VSMCs, corylin inhibited TNF-α-induced monocyte adhesion by suppressing ROS production, mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB p65 translocation. In platelet-derived growth factor-BB (PDGF-BB)-induced VSMCs, corylin inhibited PDGF-BB-induced VSMC proliferation and migration through regulating the mammalian target of rapamycin (mTOR)/dynamin-1-like protein 1 (Drp1) signaling cascade. In addition, corylin treatment not only attenuated atherosclerotic lesions, ROS production, vascular cell adhesion protein-1 (VCAM-1) expression, monocyte adhesion and VSMC proliferation in apolipoprotein E (ApoE)-deficient mice but also inhibited neointimal hyperplasia in endothelial-denuded mice. Thus, corylin may be a potential prevention and treatment for atherosclerosis.

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Naringenin inhibits TNF-α induced VSMC proliferation and migration via induction of HO-1

Food and Chemical Toxicology ◽

10.1016/j.fct.2012.06.006 ◽

2012 ◽

Vol 50 (9) ◽

pp. 3025-3031 ◽

Cited By ~ 46

Author(s):

Siyu Chen ◽

Yan Ding ◽

Weiwei Tao ◽

Wenxiang Zhang ◽

Tingming Liang ◽

...

Keyword(s):

Vsmc Proliferation ◽

Tnf Α ◽

And Migration ◽

Proliferation And Migration

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BMP-Induced MicroRNA-101 Expression Regulates Vascular Smooth Muscle Cell Migration

International Journal of Molecular Sciences ◽

10.3390/ijms21134764 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4764

Author(s):

Nanju Park ◽

Hara Kang

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Molecular Mechanisms ◽

Bmp Signaling ◽

Vsmc Proliferation ◽

Cellular Processes ◽

Vessel Development ◽

Novel Target ◽

And Migration ◽

Proliferation And Migration

Proliferation and migration of vascular smooth muscle cells (VSMCs) are implicated in blood vessel development, maintenance of vascular homeostasis, and pathogenesis of vascular disorders. MicroRNAs (miRNAs) mediate the regulation of VSMC functions in response to microenvironmental signals. Because a previous study reported that miR-101, a tumor-suppressive miRNA, is a critical regulator of cell proliferation in vascular disease, we hypothesized that miR-101 controls important cellular processes in VSMCs. The present study aimed to elucidate the effects of miR-101 on VSMC function and its molecular mechanisms. We revealed that miR-101 regulates VSMC proliferation and migration. We showed that miR-101 expression is induced by bone morphogenetic protein (BMP) signaling, and we identified dedicator of cytokinesis 4 (DOCK4) as a novel target of miR-101. Our results suggest that the BMP–miR-101–DOCK4 axis mediates the regulation of VSMC function. Our findings help further the understanding of vascular physiology and pathology.

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Micro-RNA-1 is decreased by hypoxia and contributes to the development of pulmonary vascular remodeling via regulation of sphingosine kinase 1

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00057.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. L461-L472 ◽

Cited By ~ 13

Author(s):

Justin R. Sysol ◽

Jiwang Chen ◽

Sunit Singla ◽

Shuangping Zhao ◽

Suzy Comhair ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Molecular Mechanisms ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

Pulmonary Vascular Remodeling ◽

Micro Rnas ◽

And Migration ◽

Proliferation And Migration

Sphingosine kinase 1 (SphK1) upregulation is associated with pathologic pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), but the mechanisms controlling its expression are undefined. In this study, we sought to characterize the regulation of SphK1 expression by micro-RNAs (miRs). In silico analysis of the SphK1 3′-untranslated region identified several putative miR binding sites, with miR-1-3p (miR-1) being the most highly predicted target. Therefore we further investigated the role of miR-1 in modulating SphK1 expression and characterized its effects on the phenotype of pulmonary artery smooth muscle cells (PASMCs) and the development of experimental pulmonary hypertension in vivo. Our results demonstrate that miR-1 is downregulated by hypoxia in PASMCs and can directly inhibit SphK1 expression. Overexpression of miR-1 in human PASMCs inhibits basal and hypoxia-induced proliferation and migration. Human PASMCs isolated from PAH patients exhibit reduced miR-1 expression. We also demonstrate that miR-1 is downregulated in mouse lung tissues during experimental hypoxia-mediated pulmonary hypertension (HPH), consistent with upregulation of SphK1. Furthermore, administration of miR-1 mimics in vivo prevented the development of HPH in mice and attenuated induction of SphK1 in PASMCs. These data reveal the importance of miR-1 in regulating SphK1 expression during hypoxia in PASMCs. A pivotal role is played by miR-1 in pulmonary vascular remodeling, including PASMC proliferation and migration, and its overexpression protects from the development of HPH in vivo. These studies improve our understanding of the molecular mechanisms underlying the pathogenesis of pulmonary hypertension.

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MIA SH3 Domain ER Export Factor 3 Deficiency Prevents Neointimal Formation by Restoring BAT-Like PVAT and Decreasing VSMC Proliferation and Migration

Frontiers in Endocrinology ◽

10.3389/fendo.2021.748216 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu Lei ◽

Jianfei Xu ◽

Mengju Li ◽

Ting Meng ◽

Meihua Chen ◽

...

Keyword(s):

Vascular Remodeling ◽

Association Studies ◽

Neointimal Hyperplasia ◽

Vascular Diseases ◽

Genome Wide Association Studies ◽

Neointimal Formation ◽

Vsmc Proliferation ◽

And Migration ◽

Er Export ◽

Proliferation And Migration

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

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Cyr61 promotes Schwann cell proliferation and migration via αvβ3 integrin

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00360-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zhenghui Cheng ◽

Yawen Zhang ◽

Yinchao Tian ◽

Yuhan Chen ◽

Fei Ding ◽

...

Keyword(s):

Nerve Injury ◽

Peripheral Nerves ◽

Molecular Mechanisms ◽

Αvβ3 Integrin ◽

Promoting Effect ◽

Ccn Family ◽

And Migration ◽

Proliferation And Migration

Abstract Background Schwann cells (SCs) play a crucial role in the repair of peripheral nerves. This is due to their ability to proliferate, migrate, and provide trophic support to axon regrowth. During peripheral nerve injury, SCs de-differentiate and reprogram to gain the ability to repair nerves. Cysteine-rich 61 (Cyr61/CCN1) is a member of the CCN family of matrix cell proteins and have been reported to be abundant in the secretome of repair mediating SCs. In this study we investigate the function of Cyr61 in SCs. Results We observed Cyr61 was expressed both in vivo and in vitro. The promoting effect of Cyr61 on SC proliferation and migration was through autocrine and paracrine mechanisms. SCs expressed αvβ3 integrin and the effect of Cyr61 on SC proliferation and migration could be blocked via αvβ3 integrin. Cyr61 could influence c-Jun protein expression in cultured SCs. Conclusions In this study, we found that Cyr61 promotes SC proliferation and migration via αvβ3 integrin and regulates c-Jun expression. Our study contributes to the understanding of cellular and molecular mechanisms underlying SC’s function during nerve injury, and thus, may facilitate the regeneration of peripheral nerves after injury.

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Contribution of transcription factor EB to adipoRon-induced inhibition of arterial smooth muscle cell proliferation and migration

AJP Cell Physiology ◽

10.1152/ajpcell.00294.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. C1034-C1047 ◽

Cited By ~ 1

Author(s):

Yun-Ting Wang ◽

Jiajie Chen ◽

Xiang Li ◽

Michihisa Umetani ◽

Yang Chen ◽

...

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Remodeling ◽

Therapeutic Effects ◽

Transcription Factor Eb ◽

And Migration ◽

Proliferation And Migration

Abnormal vascular smooth muscle cell (SMC) dedifferentiation with increased proliferation and migration during pathological vascular remodeling is associated with vascular disorders, such as atherosclerosis and in-stent restenosis. AdipoRon, a selective agonist of adiponectin receptor, has been shown to protect against vascular remodeling by preventing SMC dedifferentiation. However, the molecular mechanisms that mediate adipoRon-induced SMC differentiation are not well understood. The present study aimed to elucidate the role of transcription factor EB (TFEB), a master regulator of autophagy, in mediating adipoRon’s effect on SMCs. In cultured arterial SMCs, adipoRon dose-dependently increased TFEB activation, which is accompanied by upregulated transcription of genes involved in autophagy pathway and enhanced autophagic flux. In parallel, adipoRon suppressed serum-induced cell proliferation and caused cell cycle arrest. Moreover, adipoRon inhibited SMC migration as characterized by wound-healing retardation, F-actin reorganization, and matrix metalloproteinase-9 downregulation. These inhibitory effects of adipoRon on proliferation and migration were attenuated by TFEB gene silencing. Mechanistically, activation of TFEB by adipoRon is dependent on intracellular calcium, but it is not associated with changes in AMPK, ERK1/2, Akt, or molecular target of rapamycin complex 1 activation. Using ex vivo aortic explants, we demonstrated that adipoRon inhibited sprouts that had outgrown from aortic rings, whereas lentiviral TFEB shRNA transduction significantly reversed this effect of adipoRon on aortic rings. Taken together, our results indicate that adipoRon activates TFEB signaling that helps maintain the quiescent and differentiated status of arterial SMCs, preventing abnormal SMC dedifferentiation. This study provides novel mechanistic insights into understanding the therapeutic effects of adipoRon on TFEB signaling and pathological vascular remodeling.

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Possible involvement of the Hedgehog and PDPK1–Akt pathways in the growth and migration of small-cell lung cancer

Journal of International Medical Research ◽

10.1177/03000605211016562 ◽

2021 ◽

Vol 49 (5) ◽

pp. 030006052110165

Author(s):

Naiwang Tang ◽

Bin Hu ◽

Yin Zhang ◽

Zhiwei Chen ◽

Ronghuan Yu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Molecular Mechanisms ◽

Patient Characteristics ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancers ◽

And Migration ◽

Proliferation And Migration

Background Small-cell lung cancer (SCLC) accounts for approximately 15% to 20% of all lung cancers, and it is the leading cause of tumor-related deaths globally. This study explored the molecular mechanisms underlying the development of SCLC. Methods The correlations of phosphoinositide-dependent kinase-1 (PDPK1), p-Akt, and Hedgehog expression with patient characteristics were analyzed using SCLC specimens, and their expression was measured in BEAS-2B cells (control) and the SCLC cell lines H82, H69, H446, H146, and H526. Transfection experiments were performed to inhibit or activate gene expression in cells. We then measured the proliferation and migration of H146 cells. Results PDPK1, p-Akt, and Hedgehog expression was significantly higher in SCLC tissues, and their expression was correlated with patient characteristics. p-Akt expression was significantly correlated with Hedgehog expression. In H146 cells, PDPK1 and p-Akt were significantly upregulated. Silencing of PDPK1 or Akt and inhibition of Hedgehog significantly inhibited the proliferation and migration of H146 cells. PDPK1 and Akt affected Hedgehog expression, but Hedgehog did not affect PDPK1 or p-Akt expression. Conclusions The interaction between the PDPK1–Akt pathway and the Hedgehog pathway influences the prognosis, growth, and migration of SCLC.

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Paradoxical role of high mobility group box 1 in glioma: a suppressor or a promoter?

Oncology Reviews ◽

10.4081/oncol.2017.325 ◽

2017 ◽

Cited By ~ 14

Author(s):

Richard A. Seidu ◽

Min Wu ◽

Zhaoliang Su ◽

Huaxi Xu

Keyword(s):

Molecular Mechanisms ◽

High Mobility ◽

Treatment Resistance ◽

High Mobility Group ◽

Tissue Invasion ◽

Self Sufficiency ◽

Glycation End Products ◽

And Migration ◽

Proliferation And Migration

Gliomas represent 60% of primary intracranial brain tumors and 80% of all malignant types, with highest morbidity and mortality worldwide. Although glioma has been extensively studied, the molecular mechanisms underlying its pathology remain poorly understood. Clarification of the molecular mechanisms involved in their development and/or treatment resistance is highly required. High mobility group box 1 protein (HMGB1) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation and migration, through receptor for advanced glycation end products and toll like receptors in a number of cancers including gliomas. It is known that excessive release of HMGB1 in cancer leads to unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis. In this review we explore the mechanisms by which HMGB1 regulates apoptosis and autophagy in glioma. We also looked at how HMGB1 mediates glioma regression and promotes angiogenesis as well as possible signaling pathways with an attempt to provide potential therapeutic targets for the treatment of glioma.

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