2,5-Dimethylcelecoxib attenuates cardiac fibrosis caused by cryoinjury-induced myocardial infarction by suppressing the fibroblast-to-myofibroblast transformation via inhibition of the TGF-β signaling pathway
2,5-Dimethylcelecoxib attenuates cardiac fibrosis caused by cryoinjury-induced myocardial infarction by suppressing the fibroblast-to-myofibroblast transformation via inhibition of the TGF-β signaling pathway
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DOI：
10.1016/j.bcp.2022.114950
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发表时间：
2022-02-09
影响因子：
5.8
通讯作者：
Takahashi-Yanaga, Fumi
中科院分区：
文献类型：
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作者：
Ikushima, Eigo;Ishikane, Shin;Takahashi-Yanaga, Fumi
我们以前报道，2，5-二甲基塞来昔布（DM-C），塞来昔布的衍生物，缺乏环氧合酶-2抑制作用，并通过激活糖原合成酶激酶-3（GSK-3）抑制心脏重塑。然而，目前尚不清楚DM-C是否能减弱成纤维细胞向肌成纤维细胞的转化（FMT），而FMT在心脏纤维化中发挥着关键作用。因此，我们使用冷冻损伤诱导的心肌梗死（CMI）小鼠模型评估了DM-C对FMT的影响。我们发现DM-C通过减少心肌纤维化减轻了心肌梗死后左室射血分数的恶化。α-平滑肌肌动蛋白（α-SMA）（肌成纤维细胞的标志物）表达水平的分析表明，DM-C降低了心脏损伤部位的FMT。为了研究DM-C减弱FMT的机制，用TGF-β刺激从心脏获得的成纤维细胞以诱导FMT，并分析DM-C的作用。DM-C抑制了α-SMA的表达以及Smad 2/3和GSK-3的磷酸化水平，表明DM-C通过激活GSK-3抑制转化生长因子（TGF）-β信号通路来抑制α-SMA表达。DM-C降低了胶原蛋白、结缔组织生长因子（CTGF）和Snail的表达，这些蛋白也被认为会加速心脏纤维化。这些结果表明，DM-C通过抑制经由GSK-3的活化的TGF-β信号传导途径来抑制CMI后损伤部位处的FMT，从而减轻心脏纤维化。因此，DM-C作为一种新型抗纤维化药物具有抗心脏病的潜力。
We previously reported that 2,5-dimethylcelecoxib (DM-C), a derivative of celecoxib, lacks cyclooxygenase-2 inhibitory effects and suppresses cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3). How -ever, it remains unclear whether DM-C attenuates fibroblast-to-myofibroblast transformation (FMT), which plays a key role in cardiac fibrosis. Therefore, we evaluated the effect of DM-C on FMT using a cryoinjury-induced myocardial infarction (CMI) mouse model. We found that DM-C attenuated the deterioration of left ventricu-lar ejection fraction after CMI by decreasing cardiac fibrosis. Analysis of the expression level of alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblasts, indicated that DM-C decreased FMT at the cardiac injury site. To investigate the mechanism by which DM-C attenuated FMT, fibroblasts obtained from the heart were stimulated with TGF-beta to induce FMT, and the effect of DM-C was analyzed. DM-C suppressed the expression of alpha-SMA and the phosphorylation levels of Smad 2/3 and GSK-3, indicating that DM-C suppressed alpha-SMA expression by inhibiting the transforming growth factor (TGF)-beta signaling pathway via activation of GSK-3. DM-C decreased the expression of collagen, connective tissue growth factor (CTGF) and Snail, which are also known to accelerate cardiac fibrosis. These results suggested that DM-C attenuated cardiac fibrosis by suppressing FMT at the injured site after CMI by inhibiting the TGF-beta signaling pathway via activation of GSK-3. Thus, DM-C has potential against cardiac disease as a novel anti-fibrotic agent.