Mechanisms of aortic dissection smooth muscle cell phenotype switch

An, Zhen; Yang, Lei; Song, Zhigang; Tang, Hao; Yuan, Yuan; Zhao, Xu

doi:10.1016/j.jtcvs.2017.05.066

Cited by 44 publications

(30 citation statements)

References 33 publications

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“…In the pathogenesis of TAD, vascular smooth muscle cells (VSMCs) play an important role in the process of aortic wall contraction and synthesis in the presence of the stimulation of various cells to promote vascular remodeling [5]. With the phenotypic change, VSMCs transform from contraction (differentiation) phenotype to synthesis (dedifferentiation) phenotype [6,7]. Dedifferentiated VSMCs showed higher viability in terms of proliferation, migration and synthesis, and at the same time, the expressions of differentiation markers α-SMA and SM22α were down-regulated [6].…”

Section: Introductionmentioning

confidence: 99%

“…With the phenotypic change, VSMCs transform from contraction (differentiation) phenotype to synthesis (dedifferentiation) phenotype [6,7]. Dedifferentiated VSMCs showed higher viability in terms of proliferation, migration and synthesis, and at the same time, the expressions of differentiation markers α-SMA and SM22α were down-regulated [6]. In addition, ECM is the main component that forms the morphology of the aortic blood vessel wall, and in the vascular wall tissues of TAD patients, ECM shows obvious abnormalities [8].…”

Section: Introductionmentioning

confidence: 99%

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LncRNA H19 regulates smooth muscle cell functions and participates in the development of aortic dissection through sponging miR-193b-3p

et al. 2021

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Background: Multiple studies showed that long-chain noncoding RNA H19 (LncRNA H19) is high-expressed in human and mouse abdominal aortic aneurysms (AAAs). We speculated that it plays an important role in arterial disease, and therefore studied the role and mechanism of H19 in aortic dissection (AD). Methods: The expressions of related genes in human aortic smooth muscle cells (HASMCs) induced by platelet-derived growth factor BB (PDGF-BB) or in the aortic tissue of AD patients/mice were identified by Western blot and quantitative real-time polymerase chain reaction. The targeting relationship between H19 and miR-193b-3p was predicted and verified by bioinformatics analysis, dual luciferase assay, RNA pull-down assay, RNA immunoprecipitation (RIP), and Pearson correlation coefficient. The H19 and miR-193b-3p effects on the biological functions of tissues and cells were examined by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, thiazolyl blue tetrazolium bromide) assay, wound-healing assay, and Hematoxylin–Eosin (HE) staining. Results: LncRNA H19 was abnormally high-expressed in thoracic aorta tissues of AD patients, and it could competitively bind to and inhibit miR-193b-3p. In the PDGF-BB group, the expressions of H19, matrix metallopeptidase (MMP) 2 (MMP-2) and MMP-9 were up-regulated and the expressions of miR-193b-3p, α-SMA, and SM22α were down-regulated; moreover, the proliferation and migration rate of HASMCs were increased. However, H19 silencing reversed the regulation of PDGF-BB on HASMCs. More interestingly, miR-193b-3p inhibitor could partially reverse the effect of H19 silencing. In addition, the above results were verified by animal experiments, showing that shH19 and up-regulated miR-193b-3p could significantly reduce the thoracic aorta pathological damage in AD mice. Conclusion: LncRNA H19 regulated smooth muscle cell function by sponging miR-193b-3p and it participated in the development of AD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LncRNA H19 regulates smooth muscle cell functions and participates in the development of aortic dissection through sponging miR-193b-3p

et al. 2021

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“…Several previous studies confirmed that phenotypic transformation of SMCs from the contractile to synthetic type is one of the typical events in the development of AD (27,28). The increase of migration ability is the embodiment of the synthetic type, accompanied by the secretion of matrix metalloproteinases and a decline in contractile capability (29,30). Thus, downregulated FLNA expression in AD patients may be involved in the regulation of migration ability, phenotype transformation, and ECM secretion by VSMCs.…”

Section: Discussionmentioning

confidence: 68%

Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection

Chen

Wei

Zhang

et al. 2021

Front. Cardiovasc. Med.

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Filamins (FLNs) are actin cross-linking proteins, and as scaffolding proteins, FLNs are closely associated with the stabilization of the cytoskeleton. Nevertheless, the biological importance of FLNs in aortic dissection (AD) has not been well-elucidated. In this study, we first reanalyzed datasets downloaded from the Gene Expression Omnibus (GEO) database, and we found that in addition to the extracellular matrix, the actin cytoskeleton is a key structure associated with AD. Given that FLNs are involved in remodeling the cytoskeleton to affect cellular functions, we measured their expression levels in the aortas of patients with Stanford type A AD (TAAD). Our results showed that the mRNA and protein levels of FLNA were consistently decreased in dissected aortas of both humans and mice, while the FLNB protein level was upregulated despite decreased FLNB mRNA levels, and comparable expression levels of FLNC were observed between groups. Furthermore, the immunohistochemistry results demonstrated that FLNA was highly expressed in smooth muscle cells (SMCs) of aorta in non-AD samples, and downregulated in the medial layer of the dissected aortas of humans and mice. Moreover, we revealed that FOS and JUN, forming a dimeric transcription factor called AP-1 (activating protein-1), were positively correlated with the expression of FLNA in aorta. Either overexpression of FOS or JUN alone, or overexpression of FOS and JUN together, facilitated the expression of FLNA in primary cultured human aortic SMCs. In the present study, we not only detected the expression pattern of FLNs in aortas of humans and mice with or without AD, but we also found that the expression of FLNA in the AD samples was significantly reduced and that AP-1 might regulate the expression of FLNA. Our findings will contribute to the elucidation of the pathological mechanisms of AD and provide potential therapeutic targets for AD.

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“…Aortic dissection specimens were obtained during the Bentall procedures or other large vessel replacements of TAD patients. Patients with traumatic aortic injury, inflammatory aortic disease, Ehlers-Danlos syndrome, Marfan syndrome, and other connective tissue disorders were excluded (17). Control aortic specimens were obtained from patients who underwent aortic valve replacement without vascular wall lesion.…”

Section: Tissue Collectionmentioning

confidence: 99%

Long non-coding RNA RP11-465L10.10 promotes vascular smooth muscle cells phenotype switching and MMP9 expression via the NF-κB pathway

Yang¹,

Huang²,

Yu³

et al. 2021

Ann Transl Med

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Background: Thoracic aortic aneurysm/dissection (TAA/D) are complicated vascular disorders with rapid development and high mortality. Vascular smooth muscle cells (VSMCs) phenotype switching plays an important role in the pathological process of TAA/D. Previous studies have indicated a potential correlation between long non-coding RNA (lncRNA) RP11-465L10.10 and matrix metallopeptidase 9 (MMP9) involved in the development of TAA/D. This study aims to investigate the role of lncRNA RP11-465L10.10 in VSMCs phenotype switching and the molecular mechanism in regulating MMP9 expression. Methods: The expression of RP11-465L10.10 in vascular tissues and in VMSCs was detected by RT-qPCR. To investigate the role of RP11-465L10.10 on VSMCs phenotype switching, an RP11-465L10.10overexpressed lentiviral vector was constructed and transfected into VSMCs. Through EdU staining, migration assay, flow cytometry analysis, the roles of RP11-465L10.10 were estimated. Bioinformatics indicated that RP11-465L10.10 upregulating MMP9 expression via NF-κB signaling, and SN50 (a specific inhibitor of NF-κB pathway) was used to inhibit the NF-κB pathway activation, then the expression of MMP9 was detected in RP11-465L10.10 overexpressed VMSCs. Results: In this study, we found RP11-465L10.10 and MMP9 were highly increased in TAD patient tissues, which was consistent in angiotensin II-induced VSMCs phenotype switching. RP11-465L10.10 overexpression facilitated VSMCs phenotype switching and MMP9 expression. Mechanismly, NF-κB signal pathway was involved in RP11-465L10.10 induced VSMCs phenotype switching and MMP9 expression by transcriptome data analysis and experimental confirm. Conclusion: This study demonstrated that RP11-465L10.10 induces VSMCs phenotype switching and MMP9 expression via the NF-κB signal pathway, suggesting that RP11-465L10.10 might be a potential therapeutic target for TAA/D treatment.

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Mechanisms of aortic dissection smooth muscle cell phenotype switch

Abstract: Our study suggests that NANOG is highly expressed in TAD aortic wall and VSMCs. Increased NANOG promotes VSMCs phenotype switch by directly up-regulating OPN through binding to its promoter region.

Cited by 44 publications

References 33 publications

LncRNA H19 regulates smooth muscle cell functions and participates in the development of aortic dissection through sponging miR-193b-3p

LncRNA H19 regulates smooth muscle cell functions and participates in the development of aortic dissection through sponging miR-193b-3p

Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection

Long non-coding RNA RP11-465L10.10 promotes vascular smooth muscle cells phenotype switching and MMP9 expression via the NF-κB pathway

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