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Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice.

ABSTRACT: Abdominal aortic aneurysm (AAA) is characterized as a progressive dilation and degradation of the aortic wall, associated with activation of matrix metalloproteinases (MMPs) and inflammation. Emerging evidence indicates a role for microRNAs (miRNAs) in AAA pathogenesis, but it is unclear whether abdominal aortic endothelial miRNAs play a role in the disease process. We aimed to identify miRNAs in the abdominal aortic endothelium that play a critical role in AAA development.The mouse model of AAA induced by angiotensin II infusion was used in this study. Through a miRNA array and validation study, we initially identified the murine-specific miR-712 and subsequently its human/murine homolog miR-205 as angiotensin II-induced miRNAs in the abdominal aortic endothelium in vivo and in vitro. Mechanistically, miR-712 stimulated MMP activity in the aortic wall by directly targeting 2 MMP inhibitors: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing cysteine-rich protein with kazal motifs (RECK). Silencing of miR-712 and miR-205 by using anti-miR-712 and anti-miR-205, respectively, significantly decreased the aortic MMP activity and inflammation, preventing AAA development in angiotensin II-infused ApoE(-/-) mice. Further, upregulation of 4 angiotensin II-sensitive miRNAs, miR-205, -21, -133b, and -378, identified in this murine study were confirmed in human AAA samples compared with nondiseased control.Our results demonstrate that angiotensin II-sensitive miR-712 and its human homolog miR-205 downregulate TIMP3 and RECK, which in turn stimulate aortic MMP activity and inflammation, leading to AAA development. Targeting these miRNAs may be a novel therapeutic strategy to prevent AAA.

SUBMITTER: Kim CW

PROVIDER: S-EPMC4111131 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice.

Kim Chan Woo CW Kumar Sandeep S Son Dong Ju DJ Jang In-Hwan IH Griendling Kathy K KK Jo Hanjoong H

Arteriosclerosis, thrombosis, and vascular biology 20140508 7

<h4>Objective</h4>Abdominal aortic aneurysm (AAA) is characterized as a progressive dilation and degradation of the aortic wall, associated with activation of matrix metalloproteinases (MMPs) and inflammation. Emerging evidence indicates a role for microRNAs (miRNAs) in AAA pathogenesis, but it is unclear whether abdominal aortic endothelial miRNAs play a role in the disease process. We aimed to identify miRNAs in the abdominal aortic endothelium that play a critical role in AAA development.<h4> ...[more]

PMID: 24812324

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Project description:RationaleBlood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease.ObjectiveTo test whether and how eosinophils affect AAA growth.Methods and resultsPopulation-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 109/L, P<0.001). Univariate (odds ratio, 1.381, P<0.001) and multivariate (odds ratio, 1.237, P=0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in Apoe-/- and eosinophil-deficient Apoe-/-ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13-/- mice, but not eosinophil from Il4-/- mice, blocked AAA growth in Apoe-/-ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells.ConclusionsEosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

Dataset Information

Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice.

Publications

Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice.

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