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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.

ABSTRACT: 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.

SUBMITTER: Zhao F

PROVIDER: S-EPMC7185088 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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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.

Zhao Feng F Chen Tongyun T Jiang Nan N

Experimental and therapeutic medicine 20200323 6

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 upregula ...[more]

PMID: 32346440

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Project description:BackgroundHepcidin is a liver-derived hormone that controls systemic iron homeostasis, by inhibiting the iron exporter ferroportin in the gut and spleen, respective sites of iron absorption and recycling. Hepcidin is also expressed ectopically in the context of cardiovascular disease. However, the precise role of ectopic hepcidin in underlying pathophysiology is unknown. In patients with abdominal aortic aneurysm (AAA), hepcidin is markedly induced in smooth muscle cells (SMCs) of the aneurysm wall and inversely correlated with the expression of LCN2 (lipocalin-2), a protein implicated in AAA pathology. In addition, plasma hepcidin levels were inversely correlated with aneurysm growth, suggesting hepcidin has a potential disease-modifying role.MethodsTo probe the role of SMC-derived hepcidin in the setting of AAA, we applied AngII (Angiotensin-II)-induced AAA model to mice harbouring an inducible, SMC-specific deletion of hepcidin. To determine whether SMC-derived hepcidin acted cell-autonomously, we also used mice harboring an inducible SMC-specific knock-in of hepcidin-resistant ferroportinC326Y. The involvement of LCN2 was established using a LCN2-neutralizing antibody.ResultsMice with SMC-specific deletion of hepcidin or knock-in of hepcidin-resistant ferroportinC326Y had a heightened AAA phenotype compared with controls. In both models, SMCs exhibited raised ferroportin expression and reduced iron retention, accompanied by failure to suppress LCN2, impaired autophagy in SMCs, and greater aortic neutrophil infiltration. Pretreatment with LCN2-neutralizing antibody restored autophagy, reduced neutrophil infiltration, and prevented the heightened AAA phenotype. Finally, plasma hepcidin levels were consistently lower in mice with SMC-specific deletion of hepcidin than in controls, indicating that SMC-derived hepcidin contributes to the circulating pool in AAA.ConclusionsHepcidin elevation in SMCs plays a protective role in the setting of AAA. These findings are the first demonstration of a protective rather than deleterious role for hepcidin in cardiovascular disease. They highlight the need to further explore the prognostic and therapeutic value of hepcidin outside disorders of iron homeostasis.

Project description:BackgroundAbdominal aortic aneurysms (AAAs) represent a complex multifactorial hemodynamic, thrombotic, and inflammatory process that can ultimately result in aortic rupture and death. Despite improved screening and surgical management of AAAs, the mortality rates have remained high after rupture, and little progress has occurred in the development of nonoperative treatments. Intraluminal thrombus (ILT) is present in most AAAs and might be involved in AAA pathogenesis. The present review examined the latest clinical and experimental evidence for possible involvement of the ILT in AAA growth and rupture.MethodsA literature review was performed after a search of the PubMed database from 2012 to June 2020 using the terms "abdominal aortic aneurysm" and "intraluminal thrombus."ResultsThe structure, composition, and hemodynamics of ILT formation and propagation were reviewed in relation to the hemostatic and proteolytic factors favoring ILT deposition. The potential effects of the ILT on AAA wall degeneration and rupture, including a review of the current controversies regarding the position, thickness, and composition of ILT, are presented. Although initially potentially protective against increased wall stress, increasing evidence has shown that an increased volume and greater age of the ILT have direct detrimental effects on aortic wall integrity, which might predispose to an increased rupture risk.ConclusionsILT does not appear to be an innocent bystander in AAA pathophysiology. However, its exact role remains elusive and controversial. Despite computational evidence of a possible protective role of the ILT in reducing wall stress, increasing evidence has shown that the ILT promotes AAA wall degeneration in humans and in animal models. Further research, with large animal models and with more chronic ILT is crucial for a better understanding of the role of the ILT in AAAs and for the potential development of targeted therapies to slow or halt AAA progression.

Dataset Information

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.

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.

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