Chan Woo Kim1, Sandeep Kumar1, Dong Ju Son1, In-Hwan Jang1, Kathy K Griendling1, Hanjoong Jo2. 1. From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.). 2. From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.). hjo@bme.gatech.edu.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: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. APPROACH AND RESULTS: 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 humanAAA samples compared with nondiseased control. CONCLUSIONS: 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.
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