A potential antifibrotic mechanism in pathological myocardial remodeling is the recruitment of beneficial functional subpopulations of macrophages or the transformation of their phenotype. Macrophages are required to activate molecular cascades that regulate fibroblast behavior. Identifying mediators that activate the antifibrotic macrophage phenotype is tantamount to identifying the button that retards pathological remodeling of the myocardium; however, relevant studies are inadequate. Circulating renalase (RNLS) is mainly of renal origin, and cardiac myocytes also secrete it autonomously. Our previous studies revealed that RNLS delivers cell signaling to exert multiple cardiovascular protective effects, including the improvement of myocardial ischemia, and heart failure. Here, we further investigated the potential mechanism by which macrophage phenotypic transformation is targeted by RNLS to mediate stress load-induced myocardial fibrosis. Mice subjected to transverse aortic constriction (TAC) were used as a model of myocardial fibrosis. The co-incubation of macrophages and cardiac fibroblasts was used to study intercellular signaling. The results showed that RNLS co-localized with macrophages and reduced protein expression after cardiac pressure overload. TAC mice exhibited improved cardiac function and alleviated left ventricular fibrosis when exogenous RNLS was administered. Flow sorting showed that RNLS is essential for macrophage polarization towards a restorative phenotype (M2-like), thereby inhibiting myofibroblast activation, as proven by both mouse RAW264.7 and bone marrow-derived macrophage models. Mechanistically, we found that activated protein kinase B is a major pathway by which RNLS promotes M2 polarization in macrophages. RNLS may serve as a prognostic biomarker and a potential clinical candidate for the treatment of myocardial fibrosis.

中文翻译：

---

肾酶介导巨噬细胞与成纤维细胞的串扰，以减轻压力超负荷引起的病理性心肌纤维化。

病理性心肌重塑中潜在的抗纤维化机制是巨噬细胞有益功能亚群的募集或其表型的转变。巨噬细胞需要激活调节成纤维细胞行为的分子级联反应。识别出激活抗纤维化巨噬细胞表型的介质就等于识别出阻碍心肌病理重塑的按钮。然而，相关研究还不够充分。循环肾酶（RNLS）主要来源于肾脏，心肌细胞也自主分泌。我们之前的研究表明，RNLS 传递细胞信号传导，发挥多种心血管保护作用，包括改善心肌缺血和心力衰竭。在这里，我们进一步研究了 RNLS 靶向巨噬细胞表型转化介导应激负荷诱导的心肌纤维化的潜在机制。使用横向主动脉缩窄（TAC）的小鼠作为心肌纤维化模型。巨噬细胞和心脏成纤维细胞的共孵育用于研究细胞间信号传导。结果表明，RNLS 与巨噬细胞共定位，并在心脏压力超负荷后降低蛋白表达。当给予外源性 RNLS 时，TAC 小鼠表现出改善的心功能并减轻了左心室纤维化。流式分选表明，RNLS 对于巨噬细胞极化为恢复性表型（M2 样）至关重要，从而抑制肌成纤维细胞活化，小鼠 RAW264.7 和骨髓源性巨噬细胞模型都证明了这一点。从机制上讲，我们发现激活的蛋白激酶 B 是 RNLS 促进巨噬细胞 M2 极化的主要途径。RNLS 可作为预后生物标志物和治疗心肌纤维化的潜在临床候选物。