Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 04401, Republic of Korea.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, 04401, Republic of Korea; Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, 31151, Republic of Korea.
Biochem Biophys Res Commun. 2020 Apr 30;525(2):354-359. doi: 10.1016/j.bbrc.2020.02.090. Epub 2020 Feb 21.
Ischemic injury is a major risk factor for fibrosis. However, the precise mechanisms by which fibrosis is regulated and induced under ischemic oxidative stress conditions are unknown. To address this, we investigated the effect of melatonin on ischemia-induced fibrosis. In a hindlimb ischemia mouse model, ischemia induced fibrosis by increasing inflammation and the expression of extracellular matrix (ECM) proteins. Melatonin prevented ischemia-induced fibrosis in the injured tissues. In particular, melatonin suppressed the fibrosis-mediated inflammatory reaction in myoblasts through the microRNA-149 (miR-149)/indoleamine 2,3-dioxygenase-1 (IDO-1) signaling pathway. The melatonin-induced increase in miR-149 inhibited the expression of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and ECM components, such as collagen I and fibronectin. In addition, melatonin increased antioxidative activity and mitochondrial function in myoblasts via the miR-149/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) signaling axis, and the anti-fibrotic effects of melatonin were blocked by inhibition of miR-149. These findings indicate that melatonin is a key target molecule in fibrosis related to ischemic diseases and that miR-149 might be a novel target for the treatment of ischemia-induced fibrosis.
缺血性损伤是纤维化的一个主要危险因素。然而，在缺血氧化应激条件下，纤维化是如何被调控和诱导的，其确切机制尚不清楚。为了解决这个问题，我们研究了褪黑素对缺血诱导的纤维化的影响。在一种后肢缺血的小鼠模型中，缺血通过增加炎症和细胞外基质（ECM）蛋白的表达来诱导纤维化。褪黑素可预防损伤组织中的缺血诱导性纤维化。特别是，褪黑素通过 microRNA-149（miR-149）/吲哚胺 2,3-双加氧酶-1（IDO-1）信号通路抑制肌成纤维细胞中纤维化介导的炎症反应。褪黑素诱导的 miR-149 增加抑制了促炎细胞因子肿瘤坏死因子-α（TNF-α）和 ECM 成分如胶原 I 和纤维连接蛋白的表达。此外，褪黑素通过 miR-149/过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）信号轴增加肌成纤维细胞中的抗氧化活性和线粒体功能，并且 miR-149 的抑制阻断了褪黑素的抗纤维化作用。这些发现表明，褪黑素是与缺血性疾病相关的纤维化的关键靶标分子，miR-149 可能是治疗缺血诱导性纤维化的一种新的靶标。
