Wei Shuoyu, Isagawa Takayuki, Eguchi Masamichi, Sato Daisuke, Tsukano Hiroto, Miyata Keishi, Oike Yuichi, Takeda Norihiko, Ikeda Satoshi, Kawano Hiroaki, Maemura Koji
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki 852-8501, Japan.
Center for Data Science, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
Biomedicines. 2020 Nov 3;8(11):470. doi: 10.3390/biomedicines8110470.
Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases -3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage -3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. -acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.
动脉粥样硬化区域的巨噬细胞产生基质金属蛋白酶（MMPs）并降低斑块稳定性。动脉粥样硬化区域动脉壁的组织氧张力降低。缺氧诱导因子（HIF）-1α在缺氧诱导基因的转录激活中起关键作用。然而，HIF-1α独立途径在缺氧反应中的精确作用在很大程度上尚不清楚。黄嘌呤氧化酶（XO）是一种利用分子氧并产生活性氧（ROS）的酶。在此，我们表明源自XO的ROS增加小鼠巨噬细胞中-3、-10和-13的表达。我们发现巨噬细胞-3、-10和-13的转录水平在缺氧条件下升高。缺氧诱导HIF-1α缺陷型巨噬细胞中MMP表达。N-乙酰半胱氨酸（NAC）或XO抑制剂非布司他抑制小鼠巨噬细胞中MMP表达。非布司他降低载脂蛋白E缺陷小鼠的斑块破裂发生率。我们的结果表明，非布司他通过抑制巨噬细胞MMP-9和-13的活性来稳定动脉粥样硬化斑块。给予非布司他是动脉粥样硬化患者管理中的一种潜在治疗选择。
