Tetsushi Nakao1, Takahiro Horie1, Osamu Baba1, Masataka Nishiga1, Tomohiro Nishino1, Masayasu Izuhara1, Yasuhide Kuwabara1, Hitoo Nishi1, Shunsuke Usami1, Fumiko Nakazeki1, Yuya Ide1, Satoshi Koyama1, Masahiro Kimura1, Naoya Sowa1, Satoko Ohno1, Hiroki Aoki1, Koji Hasegawa1, Kazuhisa Sakamoto1, Kenji Minatoya1, Takeshi Kimura1, Koh Ono2. 1. From the Departments of Cardiovascular Medicine (T.N., T.H., O.B., M.N., T.N., M.I., Y.K., H.N., S.U., F.N., Y.I., S.K., M.K., N.S., T.K., K.O.) and Cardiovascular Surgery (K.S., K.M.), Graduate School of Medicine, Kyoto University, Japan; The Cardiovascular Research Institute, Kurume University, Japan (S.O., H.A.); and Division of Translational Research, National Hospital Organization, Kyoto Medical Center, Japan. 2. From the Departments of Cardiovascular Medicine (T.N., T.H., O.B., M.N., T.N., M.I., Y.K., H.N., S.U., F.N., Y.I., S.K., M.K., N.S., T.K., K.O.) and Cardiovascular Surgery (K.S., K.M.), Graduate School of Medicine, Kyoto University, Japan; The Cardiovascular Research Institute, Kurume University, Japan (S.O., H.A.); and Division of Translational Research, National Hospital Organization, Kyoto Medical Center, Japan. kohono@kuhp.kyoto-u.ac.jp.
Abstract
OBJECTIVE: Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. APPROACH AND RESULTS: MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II- and calcium chloride-induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride-induced AAA walls in miR-33-/- mice. In vitro experiments revealed that peritoneal macrophages from miR-33-/- mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33-/- mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33-/- mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33-deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation. CONCLUSIONS: These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA.
OBJECTIVE:Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. APPROACH AND RESULTS: MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II- and calcium chloride-induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride-induced AAA walls in miR-33-/- mice. In vitro experiments revealed that peritoneal macrophages from miR-33-/- mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33-/- mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33-/- mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33-deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation. CONCLUSIONS: These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA.
Authors: Ying H Shen; Scott A LeMaire; Nancy R Webb; Lisa A Cassis; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2020-02-26 Impact factor: 8.311
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