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.
Keywords: Anti-inflammation; Fibrosis; Ischemia; Myoblast; PGC-1α; miR-149.
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