Dataset Information

MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression.

ABSTRACT: Abdominal aortic aneurysm (AAA) is a serious vascular disease featured by inflammatory infiltration in aortic wall, aortic dilatation and extracellular matrix (ECM) degradation. Dysregulation of microRNAs (miRNAs) is implicated in AAA progress. By profiling miRNA expression in mouse AAA tissues and control aortas, we noted that miR-126a-5p was down-regulated by 18-fold in AAA samples, which was further validated with real-time qPCR. This study was performed to investigate miR-126a-5p's role in AAA formation. In vivo, a 28-d infusion of 1 ?g/kg/min Angiotensin (Ang) II was used to induce AAA formation in Apoe-/- mice. MiR-126a-5p (20 mg/kg; MIMAT0000137) or negative control (NC) agomirs were intravenously injected to mice on days 0, 7, 14 and 21 post-Ang II infusion. Our data showed that miR-126a-5p overexpression significantly improved the survival and reduced aortic dilatation in Ang II-infused mice. Elastic fragment and ECM degradation induced by Ang II were also ameliorated by miR-126a-5p. A strong up-regulation of ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS-4), a secreted proteinase that regulates matrix degradation, was observed in smooth muscle cells (SMCs) of aortic tunica media, which was inhibited by miR-126a-5p. Dual-luciferase results demonstrated ADAMTS-4 as a new and valid target for miR-126a-5p. In vitro, human aortic SMCs (hASMCs) were stimulated by Ang II. Gain- and loss-of-function experiments further confirmed that miR-126-5p prevented Ang II-induced ECM degradation, and reduced ADAMTS-4 expression in hASMCs. In summary, our work demonstrates that miR-126a-5p limits experimental AAA formation and reduces ADAMTS-4 expression in abdominal aortas.

SUBMITTER: Li L

PROVIDER: S-EPMC7348185 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression.

Li Lei L Ma Wei W Pan Shuang S Li Yongqi Y Wang Han H Wang Biao B Khalil Raouf A RA

Journal of cellular and molecular medicine 20200529 14

Abdominal aortic aneurysm (AAA) is a serious vascular disease featured by inflammatory infiltration in aortic wall, aortic dilatation and extracellular matrix (ECM) degradation. Dysregulation of microRNAs (miRNAs) is implicated in AAA progress. By profiling miRNA expression in mouse AAA tissues and control aortas, we noted that miR-126a-5p was down-regulated by 18-fold in AAA samples, which was further validated with real-time qPCR. This study was performed to investigate miR-126a-5p's role in A ...[more]

PMID: 32469162

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Project description:Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammatory cell infiltration. The present extended immunohistochemistry study aimed to characterize inflammation in AAA and aortic control samples. In specific, the composition of the infiltrating immune cells and the expression of five inflammasome components in these immune cells were evaluated, in order to characterize their role in AAA development. A total of 104 biopsies from 48 AAA patients and 40 healthy specimens from organ donors were evaluated for their grade of inflammation. Infiltrating leukocytes were characterized by specific markers (CD3, CD20 and CD68), intramural localization and inflammasome protein expression [NLR family pyrin domain containing 3 (NLRP3), absent in melanoma 2 (AIM2), apoptosis?associated speck?like protein containing a caspase recruitment domain (ASC), Caspase?1 and Caspase?5]. Macrophages, B and T lymphocytes were detected to a similar extent in grade 1, 2 and 3 AAA specimens, whereas in control samples, B and T lymphocytes were rarely observed in grade 1 lesions. Expression frequencies of NLRP3, AIM2 and Caspase?5 were significantly higher in grade 1 lesions of AAA samples compared with grade 1 lesions in control samples. Finally, AIM2, ASC, and Caspase?5 displayed significantly lower expression frequencies in grade 3 compared with grade 2 AAA specimens, and all inflammasome components were less frequently detected in grade 3 than in grade 1 lesions of AAA. This indicates that inflammasome activities decrease with AAA progression in infiltrating leukocytes. No statistically significant association was found for grade 2 and grade 3 lesions and total leukocyte count, C?reactive protein levels, maximal aortic diameter, plasma cholesterol level or biomechanical parameters (derived from finite element analysis) of the respective patients. Overall, the aortic wall of AAA contained lymphocytes and macrophages with different states of activity. The present data suggested that therapeutic inhibition of specific inflammasome components might counteract AAA development and progression.

Project description:RATIONALE:Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. ?-arrestin (?arr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for ?arr2 in AngII-induced AAA formation is currently unknown. OBJECTIVE:To determine whether ?arr2 played a role in AngII-induced AAA formation in mice. METHODS AND RESULTS:Treatment of ?arr2(+/+) and ?arr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that ?arr2 deficiency significantly attenuated AAA formation. ?arr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1?, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/?arr2(+/+) aortas, whereas ?arr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/?arr2(+/+) mice to the level observed in apoE(-/-)/?arr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/?arr2(+/+) aortas, and ?arr2 deficiency reduced these effects. CONCLUSIONS:?arr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, ?arr2-dependent signaling plays a major role in AngII-induced AAA formation.

Dataset Information

MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression.

Publications

MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression.

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