Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
FASEB J. 2022 Feb;36(2):e22150. doi: 10.1096/fj.202101428RR.
Appropriate fibrotic tissue formation after myocardial infarction (MI) is crucial to the maintenance of the heart's structure. M2-like macrophages play a vital role in post-MI fibrosis by activating cardiac fibroblasts. Because the mechanism by which post-MI cardiac fibrosis is regulated is not fully understood, we investigated, in vitro and in vivo, the cellular and molecular mechanisms of post-MI fibrotic tissue formation, especially those related to the regulation of cellular senescence and apoptosis. CD206 F4/80 CD11b M2-like macrophages collected from mouse hearts on post-MI day 7 showed increased expression of neuregulin 1 (Nrg1). Nrg1 receptor epidermal growth factor receptors ErbB2 and ErbB4 were expressed on cardiac fibroblasts in the infarct area. M2-like macrophage-derived Nrg1 suppressed both hydrogen peroxide-induced senescence and apoptosis of fibroblasts, whereas blockade of ErbB function significantly accelerated both processes. M2-like macrophage-derived Nrg1/ErbB/PI3K/Akt signaling, shown to be related to anti-senescence, was activated in damaged cardiac fibroblasts. Interestingly, systemic blockade of ErbB function in MI model mice enhanced senescence and apoptosis of cardiac fibroblasts and exacerbated inflammation. Further, increased accumulation of M2-like macrophages resulted in excessive post-MI progression of fibrosis in mice hearts. The molecular mechanism underlying the regulation of fibrotic tissue formation in the infarcted myocardium was shown in part to be attenuation of apoptosis and senescence of cardiac fibroblasts by the activation of Nrg1/ErbB/PI3K/Akt signaling. M2-like macrophage-mediated regulation of Nrg1/ErbB signaling has a substantial effect on fibrotic tissue formation in the infarcted adult mouse heart and is critical for suppressing the progression of senescence and apoptosis of cardiac fibroblasts.
心肌梗死后（MI）适当的纤维化组织形成对于维持心脏结构至关重要。M2 样巨噬细胞通过激活心肌成纤维细胞在 MI 后纤维化中发挥重要作用。由于 MI 后心脏纤维化的调节机制尚未完全阐明，我们在体外和体内研究了 MI 后纤维组织形成的细胞和分子机制，特别是与细胞衰老和凋亡调节相关的机制。在 MI 后第 7 天从小鼠心脏收集的 CD206+F4/80+CD11b+M2 样巨噬细胞显示出神经调节蛋白 1（Nrg1）的表达增加。Nrg1 受体表皮生长因子受体 ErbB2 和 ErbB4 在梗死区的心肌成纤维细胞上表达。M2 样巨噬细胞衍生的 Nrg1 抑制了成纤维细胞的过氧化氢诱导的衰老和凋亡，而 ErbB 功能的阻断则显著加速了这两个过程。M2 样巨噬细胞衍生的 Nrg1/ErbB/PI3K/Akt 信号通路，与抗衰老有关，在受损的心肌成纤维细胞中被激活。有趣的是，MI 模型小鼠中 ErbB 功能的系统性阻断增强了心肌成纤维细胞的衰老和凋亡，并加剧了炎症反应。此外，M2 样巨噬细胞的大量积累导致小鼠心脏中 MI 后纤维化的过度进展。部分表明，Nrg1/ErbB/PI3K/Akt 信号通路的激活通过抑制心肌成纤维细胞的凋亡和衰老来调节梗死心肌中的纤维化组织形成的分子机制。M2 样巨噬细胞介导的 Nrg1/ErbB 信号调节对梗死成年小鼠心脏中的纤维化组织形成有重大影响，并且对于抑制心肌成纤维细胞的衰老和凋亡的进展至关重要。
