The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor α (RORα), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORα is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORα. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K) / Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.

中文翻译：

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Maresin-1 通过 IGF-1 旁分泌途径诱导心肌细胞肥大

炎症的消退与组织修复密切相关。最近的研究表明，巨噬细胞通过产生称为专门的促分解介质 (SPM) 的脂质介质来抑制炎症反应。然而，SPMs 在组织修复中的生物学意义仍有待在心脏中得到充分阐明。在这项研究中，我们专注于 maresin-1 (MaR1) 并检查了 MaR1 对心肌细胞的修复作用。MaR1 处理增加了培养的新生大鼠心肌细胞中的细胞大小。由于MaR1未改变胎儿心脏基因的表达，因此MaR1诱导了生理性肥大。SR3335 是一种视黄酸相关孤儿受体 α (RORα) 的抑制剂，可减轻 MaR1 诱导的心肌细胞肥大，这与最近关于 RORα 是 MaR1 受体之一的报道一致。重要的，为了响应 MaR1，心肌细胞通过 RORα 产生 IGF-1。此外，MaR1 激活磷酸肌醇 3-激酶 (PI3K)/Akt 信号通路和渥曼青霉素（PI3K 抑制剂）或曲西瑞滨（Akt 抑制剂）消除了 MaR1 诱导的心肌细胞肥大。最后，NVP-AEW541 对 IGF-1 受体的阻断抑制了 MaR-1 诱导的心肌细胞肥大以及 PI3K/Akt 通路的激活。这些数据表明 MaR1 通过 RORα/IGF-1/PI3K/Akt 途径诱导心肌细胞肥大。考虑到 MaR1 是一种有效的解决因素，MaR1 可能是协调炎症解决与心肌修复的关键介质。Akt 抑制剂，消除了 MaR1 诱导的心肌细胞肥大。最后，NVP-AEW541 对 IGF-1 受体的阻断抑制了 MaR-1 诱导的心肌细胞肥大以及 PI3K/Akt 通路的激活。这些数据表明 MaR1 通过 RORα/IGF-1/PI3K/Akt 途径诱导心肌细胞肥大。考虑到 MaR1 是一种有效的解决因素，MaR1 可能是协调炎症解决与心肌修复的关键介质。Akt 抑制剂，消除了 MaR1 诱导的心肌细胞肥大。最后，NVP-AEW541 对 IGF-1 受体的阻断抑制了 MaR-1 诱导的心肌细胞肥大以及 PI3K/Akt 通路的激活。这些数据表明 MaR1 通过 RORα/IGF-1/PI3K/Akt 途径诱导心肌细胞肥大。考虑到 MaR1 是一种有效的解决因素，MaR1 可能是协调炎症解决与心肌修复的关键介质。