Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Division of Translational Research, National Hospital Organization, Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto, 612-8555, Japan.
Sci Rep. 2022 Jul 14;12(1):11984. doi: 10.1038/s41598-022-16017-5.
Abdominal 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 (CaCl)-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 CaCl 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.
腹主动脉瘤（AAA）是一种致命的疾病，但迄今为止尚未发现有效的治疗药物。以前，我们发现与野生型小鼠相比，miR-33 缺陷型小鼠的 AAA 形成受到抑制。小鼠只有一种 miR-33，但人类有两种 miR-33，即 miR-33a 和 miR-33b。到目前为止的数据强烈支持抑制 miR-33a 或 miR-33b 将成为治疗 AAA 的新策略。我们生成了两种可能分别抑制 miR-33a 和 miR-33b 的特异性抗 microRNA 寡核苷酸（AMO）。体外研究表明，针对 miR-33b 的 AMO 更有效；因此，我们在人源化 miR-33b 敲入小鼠的氯化钙（CaCl）诱导的 AAA 模型中检查了这种 AMO 的体内作用。在该模型中，应用抗 miR-33b 可明显改善 AAA。为了进一步阐明机制，我们在 CaCl 给药后 1 周评估了 AAA，以检查抗 miR-33b 的作用。组织学检查显示，用抗 miR-33b 处理的小鼠主动脉中 MMP-9 阳性巨噬细胞的数量和 MCP-1 水平明显降低，与用对照寡核苷酸处理的小鼠相比，血清脂质谱得到改善。这些结果支持抑制 miR-33b 可有效治疗 AAA。
