Masaki Imanishi1, Yoichi Chiba1, Noriko Tomita1, Shinji Matsunaga1, Toshitaka Nakagawa1, Masaki Ueno1, Kazuhiro Yamamoto1, Toshiaki Tamaki1, Shuhei Tomita2. 1. From the Division of Molecular Pharmacology, Faculty of Medicine, Tottori University, Japan (M.I., S.M., S.T.); Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Japan (Y.C., M.U.); Division of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Japan (N.T., K.Y.); Life Science Research Center, Kagawa University, Japan (T.N.); Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan (T.T.); and Department of Pharmacology, Faculty of Medicine, Osaka City University, Japan (S.T.). 2. From the Division of Molecular Pharmacology, Faculty of Medicine, Tottori University, Japan (M.I., S.M., S.T.); Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Japan (Y.C., M.U.); Division of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Japan (N.T., K.Y.); Life Science Research Center, Kagawa University, Japan (T.N.); Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan (T.T.); and Department of Pharmacology, Faculty of Medicine, Osaka City University, Japan (S.T.). tomita.shuhei@med.osaka-cu.ac.jp.
Abstract
OBJECTIVE: The purpose of this study was to determine the role of smooth muscle cell-derived hypoxia-inducible factor-1α (Hif-1α) in the pathogenesis of aortic aneurysms. APPROACH AND RESULTS: Control mice and smooth muscle cell-specific hypoxia-inducible factor-1α-deficient mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. Mutant mice experienced increased levels of aneurysm formation of the thoracic or abdominal aorta with more severe elastin disruption, compared with control mice. Smooth muscle cell-specific hypoxia-inducible factor-1α deficiency did not affect matrix metalloproteinase-2 activity; however, the activity of lysyl oxidase and the levels of tropoelastin mRNA in the angiotensin II- and β-aminopropionitrile-treated aortae, associated with elastin fiber formation, were suppressed. Furthermore, we observed reduced volumes of mature cross-linked elastin in the thoracoabdominal aorta after treatment with angiotensin II and β-aminopropionitrile. CONCLUSIONS: Deficiency of smooth muscle cell-derived hypoxia-inducible factor-1α augments aortic aneurysms, accompanied by disruption of elastin fiber formation, but not changes of elastin fiber degradation.
OBJECTIVE: The purpose of this study was to determine the role of smooth muscle cell-derived hypoxia-inducible factor-1α (Hif-1α) in the pathogenesis of aortic aneurysms. APPROACH AND RESULTS: Control mice and smooth muscle cell-specific hypoxia-inducible factor-1α-deficient mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. Mutant mice experienced increased levels of aneurysm formation of the thoracic or abdominal aorta with more severe elastin disruption, compared with control mice. Smooth muscle cell-specific hypoxia-inducible factor-1α deficiency did not affect matrix metalloproteinase-2 activity; however, the activity of lysyl oxidase and the levels of tropoelastin mRNA in the angiotensin II- and β-aminopropionitrile-treated aortae, associated with elastin fiber formation, were suppressed. Furthermore, we observed reduced volumes of mature cross-linked elastin in the thoracoabdominal aorta after treatment with angiotensin II and β-aminopropionitrile. CONCLUSIONS: Deficiency of smooth muscle cell-derived hypoxia-inducible factor-1α augments aortic aneurysms, accompanied by disruption of elastin fiber formation, but not changes of elastin fiber degradation.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Anna Henry Borton; Bryan L Benson; Lee E Neilson; Ashley Saunders; M Amer Alaiti; Alex Y Huang; Mukesh K Jain; Aaron Proweller; Diana L Ramirez-Bergeron Journal: J Am Heart Assoc Date: 2018-06-01 Impact factor: 5.501
Authors: Chia-Hua Wu; Shayan Mohammadmoradi; Jeff Z Chen; Hisashi Sawada; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2018-07 Impact factor: 8.311