miRNA-504 inhibits p53-dependent vascular smooth muscle cell apoptosis and may prevent aneurysm formation

Cao, Xue; Cai, Zhenguo; Liu, Junyan; Zhang, Yanru; Wang, Xin; Li, Xueqi; Xia, Hongyuan

doi:10.3892/mmr.2017.6873

Cited by 21 publications

(15 citation statements)

References 57 publications

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“…Histological studies have revealed that AAA is associated with the impairment of apoptotic and inflammatory functions of vascular smooth muscle cells (VSMCs). VSMCs are the key source of elastin, which provides the elasticity of the aortic wall (3). VSMC apoptosis can reduce the levels of elastin, leading to the expansion of the aortic wall and ultimately resulting in alterations to the elasticity and remodeling of the abdominal aortic wall (4).…”

Section: Introductionmentioning

confidence: 99%

CDR1as/miR‑7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells

2020

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Abdominal aortic aneurysm (AAA) is characterized as dilation of the aortic wall. Dysregulation of vascular smooth muscle cells (VSMCs) can contribute to the development of this phenotype. Circular RNAs and microRNAs (miRNAs) can regulate the proliferation and apoptosis of VSMCs. This present study aimed to identify the mechanisms of action behind the regulation of cerebellar degeneration-related protein 1 antisense RNA (CDR1as)/miRNA (miR)-7 in VSMCs. The expression levels of miR-7 were upregulated, whereas the levels of CDR1as and cytoskeleton-associated protein 4 (CKAP4) were downregulated in aortic specimens obtained from 10 patients who underwent surgery for AAA compared with aortic specimens from 10 control patients who underwent coronary artery bypass surgery. The molecular mechanism of action of CDR1as/miR-7 was investigated in primary VSMCs. The results of Cell Counting kit-8 and cell growth curve assays revealed that overexpression of CDR1as and knockdown of miR-7, increased VSMC proliferation, whereas knockdown of CDR1as and overexpression of miR-7 suppressed VSMC proliferation. In addition, overexpression of CDR1as and knockdown of miR-7, suppressed apoptosis in VSMCs, indicated by the decreased levels of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) activity, whereas knockdown of CDR1as and overexpression of miR-7 exhibited the opposite effects. The results of luciferase reporter and biotin pull-down assays confirmed that CDR1as directly bound to miR-7 and suppressed its expression. Additionally, the CDR1as-induced proliferation and suppressed apoptosis was reversed by the overexpression of miR-7. Furthermore, luciferase reporter, reverse transcription-quantitative PCR and western blot assays revealed that miR-7 directly targeted CKAP4 and suppressed its expression. Additionally, the miR-7-suppressed proliferation and increased ROS and LDH activity were reversed by the overexpression of CKAP4. CDR1as also decreased caspase 3/7 activity, which was reversed by miR-7 mimics. miR-7 increased the activity of caspase 3/7, which was again reversed by the overexpression of CKAP4. Therefore, CDR1as, miR-7 and CKAP4 may act in the same pathway to regulate VSMC proliferation and apoptosis.

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Section: Introductionmentioning

confidence: 99%

CDR1as/miR‑7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells

2020

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“…Therefore, searching for novel therapeutic methods is imperative to reduce mortality of this disease. AAA is a multifactorial disease characterized by extensive vascular inflammation and degenerative elasticity of aortic wall caused by vascular smooth muscle cells (VSMCs) apoptosis reduced elastin production [5,6]. Thus, inhibiting apoptosis of VSMCs and alleviating inflammation are mainstream directions for biomarkers and therapeutic approaches of AAA.…”

Section: Introductionmentioning

confidence: 99%

Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production

Xue

et al. 2019

Bioscience Reports

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Abdominal aortic aneurysm (AAA) is often clinically silent before rupture characterized by extensive vascular inflammation and degenerative elasticity of aortic wall. Monocyte chemotactic protein-induced protein-1 (MCPIP1) exhibits anti-infllammatory and pro-apoptotic effects involved in atherogenesis. However, little is known about the expression and the contribution of MCPIP1 in AAA. In the present study, we collected clinical AAA specimens and constructed AAA mice model through Ang-II infusion, and found apparently increased MCPIP1 expression and severe inflammatory infiltration in AAA aortic membrane as evidenced by elevated levels of monocyte chemotactic protein 1 (MCP-1), interleukin 1 β (IL-1β) and NF-κB, as well as HE staining. The elasticity of aortic tunica media was impaired along with multiple apoptosis of vascular smooth muscle cells (VSMCs) in Ang-II-induced aneurysmal mouse. In vitro Ang-II administration of VSMCs induced MCPIP1 expression, accompanied by up-regulation of matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, as well as enhancement of VSMCs proliferation and apoptosis, which may cause damage of intima–media elasticity. Silencing MCPIP1 reversed above effects to further restore the balance of proliferation and apoptosis in VSMCs. Overall, our data indicated that up-regulation of MCPIP1 may become a promising candidate for the diagnosis of AAA, and specific knockdown of MCPIP1 in VSMCs could inhibit VSMCs apoptosis and down-regulate MMPs to maintain vascular wall elasticity. Therefore, knockdown of MCPIP1 may serve as a potential target for gene therapy of AAA.

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“…Apoptosis-related pathways were also found in the functional enrichment analysis of target genes. (26,27). The second category of ASP is extrinsic ASP.…”

Section: Discussionmentioning

confidence: 99%

Weighted miRNA co-expression network reveals potential roles of apoptosis related pathways and crucial genes in thoracic aortic aneurysm

Chen

et al. 2021

J Thorac Dis

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Background: Thoracic aortic aneurysm (TAA) is a potentially life-threatening disease for which few medical therapies are available. Thus, it is critically important to investigate the underlying molecular mechanisms of TAA, and identify potential targets for TAA treatment. Methods: Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were screened, and a weighted correlation network analysis (WGCNA) was employed to construct a weighted miRNA co-expression network using GSE110527. The DEMs were then mapped into the whole coexpression network of all samples, and a DEM coexpression network was created. Molecular Complex Detection (MCODE) was used to identify crucial miRNAs. Target genes were predicted using the miRTarbase database, and further screened by identifying genes that overlapped with the DEGs of GSE26155. The screened target genes were validated using GSE9106, and the successfully validated genes were considered as crucial genes. Finally, a miRNA risk score for diagnosing TAA was calculated by undertaking a least absolute shrinkage and selection operator (LASSO) regression. Results: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) signaling pathway was found in DEM functional enrichment. Crucial miRNAs were identified and target genes were predicted and associated with the regulation of the TRAIL signaling pathway. Next, 113 important target genes were identified as overlapping with the DEGs of GSE26155. These genes were further validated, and 5 successfully validated genes were considered as crucial genes. Finally, the miRNA risk score calculated by the LASSO regression was shown to have potential diagnostic value. Conclusions: We performed a WGCNA analysis to construct a weighted miRNA co-expression network, predicted target genes of crucial miRNAs, identified crucial genes, and finally calculated a miRNA risk score.The results showed that pathways and genes associated with apoptosis appear to play an important role in TAA pathogenesis, and that medications targeting apoptosis might slow TAA progression. Future in vitro and in vivo experimental studies need to be undertaken to further validate our findings and investigate the mechanistic details of these crucial miRNAs and crucial genes.

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miRNA-504 inhibits p53-dependent vascular smooth muscle cell apoptosis and may prevent aneurysm formation

Cited by 21 publications

References 57 publications

CDR1as/miR‑7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells

CDR1as/miR‑7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells

Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production

Weighted miRNA co-expression network reveals potential roles of apoptosis related pathways and crucial genes in thoracic aortic aneurysm

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