Author:
Yamasaki Tomohiro,Horie Takahiro,Koyama Satoshi,Nakao Tetsushi,Baba Osamu,Kimura Masahiro,Sowa Naoya,Sakamoto Kazuhisa,Yamazaki Kazuhiro,Obika Satoshi,Kasahara Yuuya,Kotera Jun,Oka Kozo,Fujita Ryo,Sasaki Takashi,Takemiya Akihiro,Hasegawa Koji,Minatoya Kenji,Kimura Takeshi,Ono Koh
Abstract
AbstractAbdominal aortic aneurysm (AAA) is a lethal disease, but no beneficial therapeutic agents have been established to date. Previously, we found that AAA formation is suppressed in microRNA (miR)-33-deficient mice compared with wild-type mice. Mice have only one miR-33, but humans have two miR-33 s, miR-33a and miR-33b. The data so far strongly support that inhibiting miR-33a or miR-33b will be a new strategy to treat AAA. We produced two specific anti-microRNA oligonucleotides (AMOs) that may inhibit miR-33a and miR-33b, respectively. In vitro studies showed that the AMO against miR-33b was more effective; therefore, we examined the in vivo effects of this AMO in a calcium chloride (CaCl2)-induced AAA model in humanized miR-33b knock-in mice. In this model, AAA was clearly improved by application of anti-miR-33b. To further elucidate the mechanism, we evaluated AAA 1 week after CaCl2 administration to examine the effect of anti-miR-33b. Histological examination revealed that the number of MMP-9-positive macrophages and the level of MCP-1 in the aorta of mice treated with anti-miR-33b was significantly reduced, and the serum lipid profile was improved compared with mice treated with control oligonucleotides. These results support that inhibition of miR-33b is effective in the treatment for AAA.
Funder
Mochida Memorial Foundation for Medical and Pharmaceutical Research
Suzuken Memorial Foundation
Bristol Myers Squibb
Fujiwara Memorial Foundation
Japan Society for the Promotion of Science
The Vehicle Racing Commemorative Foundation
Japan Agency for Medical Research and Development
Publisher
Springer Science and Business Media LLC
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