Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Laboratory of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Indonesia, West Java, Indonesia.
Am J Physiol Cell Physiol. 2021 Jul 1;321(1):C82-C93. doi: 10.1152/ajpcell.00568.2020. Epub 2021 May 26.
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.
炎症的消退与组织修复密切相关。最近的研究表明，巨噬细胞通过产生脂质介质，即所谓的特异性促解决介质（SPM）来抑制炎症反应；然而，SPM 在心脏组织修复中的生物学意义仍有待充分阐明。在本研究中，我们专注于maresin-1（MaR1），并研究了 MaR1 在心肌细胞中的修复作用。MaR1 处理可增加培养的新生大鼠心肌细胞的细胞大小。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。视黄酸相关孤儿受体α（RORα）的抑制剂 SR3335 减轻了 MaR1 诱导的心肌细胞肥大，这与最近的一项研究报告一致，即 RORα 是 MaR1 的受体之一。重要的是，心肌细胞通过 RORα 产生 IGF-1 作为对 MaR1 的反应。此外，MaR1 激活了磷脂酰肌醇 3-激酶（PI3K）/Akt 信号通路，PI3K 抑制剂wortmannin 或 Akt 抑制剂 triciribine 可阻断 MaR1 诱导的心肌细胞肥大。最后，NVP-AEW541 通过阻断 IGF-1 受体抑制了 MaR1 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 通路诱导心肌细胞肥大。鉴于 MaR1 是一种有效的解决因素，MaR1 可能是协调炎症消退与心肌修复的关键介质。
