Aortic dissection is associated with reduced polycystin-1 expression, an abnormality that leads to increased ERK phosphorylation in vascular smooth muscle cells

Feng, Junbo; Ge, Shangqing; Zhang, L; Chen, Hong; Liang, Chaozhao

doi:10.4081/ejh.2016.2711

Cited by 15 publications

(14 citation statements)

References 30 publications

(29 reference statements)

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“…In our study, we found that the MEK–ERK1/2 signaling pathway and ATG5 and ATG7 were regulated by EZH2 at the same time, and we also did not rule out the possibility of MEK–ERK1/2 signaling regulating ATG5 and ATG7 expression or their interaction in VSMCs. On the other hand, recent studies have shown that the MEK–ERK1/2 signaling pathway is also a contributor to other pathophysiological processes of AD, including VSMC phenotype switch 39 , apoptosis 40 , and proliferation inhibition 41 . Although we have demonstrated that EZH2 has no effects on VSMC apoptosis and proliferation, whether EZH2 could regulate VSMC phenotype switch via MEK–ERK1/2 signaling remains unknown.…”

Section: Discussionmentioning

confidence: 99%

EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection

Wei

et al. 2018

Cell Death Dis

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Enhancer of zeste homolog 2 (EZH2), a methyltransferase that di- and tri-methylates lysine-27 of histone H3, largely functions as a transcriptional repressor, and plays a critical role in various kinds of cancers. Here we report a novel function of EZH2 in regulating autophagic cell death (ACD) of vascular smooth muscle cells (VSMCs) that affect aortic dissection (AD). Inhibition of EZH2 activity by UNC1999 or knockdown EZH2 resulted in VSMC loss, while overexpression of EZH2 facilitated VSMC growth, and these effects of EZH2 on VSMCs were independent of proliferation and apoptosis. Interestingly, more autophagic vacuoles and increased LC3II protein levels were identified in VSMCs with EZH2 inhibition or deficiency. Moreover, when compared with counterparts, chloroquine alone, or chloroquine with rapamycin treatment led to more LC3II accumulation in EZH2 inhibited or knockdown VSMCs, which indicated that EZH2 negatively regulated autophagosome formation. In conjunction to this, ATG5 and ATG7 protein levels were remarkably increased in EZH2 inhibited or deficient VSMCs, and ATG5 or ATG7 knockdown virtually rescued VSMC loss induced by EZH2 inhibition or knockdown. In addition, we found that the MEK–ERK1/2 signaling pathway, but not AMPKα, mTOR, or AKT pathway, is responsible for the impact of EZH2 on ACD of VSMCs. Additionally, the adverse effects of EZH2 inhibition or knockdown on VSMCs were largely reversed by PD98059, an inhibitor of MEK1. More importantly, decreased EZH2 expression levels in the aortic wall of patients with AD indicated its contribution to VSMC loss and AD occurrence. Overall, these findings revealed that EZH2 affects ACD of VSMCs and the pathologic process of AD via regulating ATG5 and ATG7 expression and MEK–ERK1/2 signaling. Our hitherto unrecognized findings indicate that EZH2 activation has therapeutic or preventive potential for AD.

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Section: Discussionmentioning

confidence: 99%

EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection

Wei

et al. 2018

Cell Death Dis

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“…Studies had shown that MYC was indeed upregulated in ATAAD [ 52 ]. MYC signaling is involved in vascular smooth muscle cell (VSMC) dysfunction, vasoconstriction, and vascular remodeling in aortic dissection [ 53 ]. ITGA2 interacts with collagen in tumors, promotes cell migration, and promotes apoptosis-free resistance [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Molecular Regulatory Features and Markers for Acute Type A Aortic Dissection

Zhang

Yan

et al. 2021

Computational and Mathematical Methods in Medicine

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Background. Acute type A aortic dissection (ATAAD) is one of the most lethal cardiovascular diseases, and its molecular mechanism remains unclear. Methods. Differentially expressed genes (DEGs) between ATAAD and control were detected by limma R package in GSE52093, GSE153434, GSE98770, and GSE84827, respectively. The coexpression network of DEGs was identified by the WGCNA package. Enrichment analysis was performed for module genes that were positively correlated with ATAAD using clusterProfiler R package. In addition, differentially methylated markers between aortic dissection and control were identified by ChAMP package. After comparing with ATAAD-related genes, a protein-protein interaction (PPI) network was established based on the STRING database. The genes with the highest connectivity were identified as hub genes. Finally, differential immune cell infiltration between ATAAD and control was identified by ssGSEA. Results. From GSE52093 and GSE153434, 268 module genes were obtained with consistent direction of differential expression and high correlation with ATAAD. They were significantly enriched in T cell activation, HIF-1 signaling pathway, and cell cycle. In addition, 2060 differentially methylated markers were obtained from GSE84827. Among them, 77 methylation markers were ATAAD-related DEGs. Using the PPI network, we identified MYC, ITGA2, RND3, BCL2, and PHLPP2 as hub genes. Finally, we identified significantly differentially infiltrated immune cells in ATAAD. Conclusion. The hub genes we identified may be regulated by methylation and participate in the development of ATAAD through immune inflammation and oxidative stress response. The findings may provide new insights into the molecular mechanisms and therapeutic targets for ATAAD.

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“…We for the first time showed that crocin suppressed ERK1/2 pathway in cultured VSMCs. The role of ERK1/2 and KLF4 in VSMCs phenotypic switch had been well established ( 32 – 35 ). We also revealed that ERK1/2 inhibitor U0126 significantly reduced p-ERK1/2 and KLF4 levels.…”

Section: Discussionmentioning

confidence: 99%

Crocin prevents platelet‑derived growth factor BB‑induced vascular smooth muscle cells proliferation and phenotypic switch

Tong

2018

Mol Med Report

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The phenotypic switch of vascular smooth muscle cells (VSMCs) is a major initiating factor for atherosclerotic cardiovascular diseases. Platelet-derived growth factor-BB (PDGF-BB) initiates a number of biological processes that contribute to VSMC proliferation and phenotypic switch. Crocin, a component of saffron, has been reported to inhibit atheromatous plaque formation. However, the effects of crocin on PDGF-BB-induced VSMC proliferation and phenotypic switch remain unclear. The aim of the present study was to investigate the role of crocin on PDGF-BB-induced VSMCs proliferation and phenotypic switch and its underlying mechanisms. Cell proliferation and markers of VSMCs phenotypic switch were measured using a Cell Counting Kit-8 assay and western blot analysis, respectively. The signaling pathways involved in the effects of crocin on VSMCs were validated by western blot analysis with or without the use of specific pathway inhibitors. Crocin significantly inhibited PDGF-BB-induced VSMCs proliferation compared with the PDGF-BB only group (P<0.05). In addition, crocin significantly abrogated the PDGF-BB-induced increase in contractile protein α-smooth muscle actin, calponin and decrease in synthetic proteins osteopontin (OPN) in a concentration dependent manner (P<0.05). In addition, crocin slowed PDGF-BB-induced Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK)/Kruppel-like factor 4 (KLF4) signaling activation in VSMCs. By applying the JAK inhibitor (AG490) and ERK1/2 inhibitor (U0126), the results suggested that the crocin inhibited PDGF-BB-induced VSMCs phenotypic switch through the JAK/STAT3 and ERK/KLF4 signaling pathways. These results suggested that crocin may effectively prevent PDGF-BB-induced VSMCs proliferation and phenotypic switch and may be a promising candidate for the therapy of atherosclerotic cardiovascular diseases.

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Aortic dissection is associated with reduced polycystin-1 expression, an abnormality that leads to increased ERK phosphorylation in vascular smooth muscle cells

Cited by 15 publications

References 30 publications

EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection

EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection

Identification of Molecular Regulatory Features and Markers for Acute Type A Aortic Dissection

Crocin prevents platelet‑derived growth factor BB‑induced vascular smooth muscle cells proliferation and phenotypic switch

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