Vermeulen Zarha, Hervent Anne-Sophie, Dugaucquier Lindsey, Vandekerckhove Leni, Rombouts Miche, Beyens Matthias, Schrijvers Dorien M, De Meyer Guido R Y, Maudsley Stuart, De Keulenaer Gilles W, Segers Vincent F M
Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
Center of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Am J Physiol Heart Circ Physiol. 2017 Nov 1;313(5):H934-H945. doi: 10.1152/ajpheart.00206.2017. Epub 2017 Aug 19.
The neuregulin-1 (NRG-1)/receptor tyrosine-protein kinase erbB (ErbB) system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies have indicated that NRG-1 has antifibrotic effects in the left ventricle, which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages. In this study, we hypothesized that the antifibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the antifibrotic effect of NRG-1 may be active in other organs, such as the skin and lung. First, in a mouse model of angiotensin II (ANG II)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (20 µg·kg·day ip) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 wk). Interestingly, 1 wk after exposure to ANG II, NRG-1 already attenuated myocardial macrophage infiltration and cytokine expression. Furthermore, mice with myeloid-specific deletion of the gene () showed an intensified myocardial fibrotic response to ANG II. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways, and reduced the release of inflammatory cytokines. Further experiments showed that the antifibrotic and anti-inflammatory effects of NRG-1 were reproducible in mouse models of bleomycin-induced dermal and pulmonary fibrosis. Overall, this study demonstrates that the antifibrotic effect of NRG-1 in the heart is linked to anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Second, this study shows that NRG-1 has antifibrotic and anti-inflammatory effects in organs other than the heart, such as the skin and lung. Our study contributes to the understanding of the antifibrotic effect of neuregulin-1 during myocardial remodeling. Here, we show that the antifibrotic effect of neuregulin-1 is at least partially mediated through anti-inflammatory activity, linked to receptor tyrosine-protein kinase erbB-4 activation in macrophages. Furthermore, we show that this effect is also present outside the heart.
神经调节蛋白-1（NRG-1）/受体酪氨酸蛋白激酶erbB（ErbB）系统是一种由内皮细胞控制的旁分泌系统，可调节心脏功能和适应性。最近的研究表明，NRG-1在左心室具有抗纤维化作用，这是通过对心脏成纤维细胞的直接作用来解释的。然而，NRG-1/ErbB系统也调节巨噬细胞的功能。在本研究中，我们假设NRG-1在心脏中的抗纤维化作用至少部分是通过对巨噬细胞的抑制作用介导的。我们还假设NRG-1的抗纤维化作用可能在其他器官（如皮肤和肺）中也具有活性。首先，在血管紧张素II（ANG II）诱导的心肌肥大和纤维化小鼠模型中，NRG-1治疗（腹腔注射20μg·kg·天）显著减轻了心肌肥大和纤维化，并改善了被动心室僵硬度（4周）。有趣的是，在暴露于ANG II后1周，NRG-1已经减轻了心肌巨噬细胞浸润和细胞因子表达。此外，髓系特异性缺失该基因（）的小鼠对ANG II表现出增强的心肌纤维化反应。一致地，NRG-1在分离的巨噬细胞中激活了ErbB4受体，抑制了磷脂酰肌醇3激酶/Akt和STAT3信号通路，并减少了炎性细胞因子的释放。进一步的实验表明，NRG-1的抗纤维化和抗炎作用在博来霉素诱导的皮肤和肺纤维化小鼠模型中是可重复的。总体而言，本研究表明，NRG-1在心脏中的抗纤维化作用与巨噬细胞中NRG-1/ErbB4信号的抗炎活性有关。其次，本研究表明NRG-1在心脏以外的器官（如皮肤和肺）中具有抗纤维化和抗炎作用。我们的研究有助于理解神经调节蛋白-1在心肌重塑过程中的抗纤维化作用。在这里，我们表明神经调节蛋白-1的抗纤维化作用至少部分是通过抗炎活性介导的，这与巨噬细胞中受体酪氨酸蛋白激酶erbB-4的激活有关。此外，我们表明这种作用在心脏外也存在。
