Effect of impaired cardiac gp130-STAT3 signaling on myeloid cells mediated inflammatory processes after myocardial infarction

心肌梗死（MI）引起的左心室重构是导致心力衰竭的原因之一。在心肌梗死、心肌肥厚和慢性心力衰竭患者中，循环IL-6型细胞因子模式的明显变化和心肌gp130受体表达水平、激活状态和相关下游信号级联的改变已被报道。STAT3是IL-6-gp130信号系统的主要下游介质，在心脏血管生成、肥大、炎症、纤维化和再生中起关键作用。在心肌梗死后的急性期和缺血/再灌注期间，STAT3的强烈激活增强了心肌细胞的存活途径，降低了氧化应激。在心肌梗死的后期，gp130介导的STAT3激活的强度被及时调节，适度的激活对于有益的代偿性肥大和血管生成至关重要。反过来，心肌梗死后gp130介导的STAT3持续高水平且不受控制的激活促进了髓系细胞（巨噬细胞、粒细胞、中性粒细胞）的持续高水平炎症。作为stat3介导的心肌梗死后心脏炎症的驱动力，我们发现了与MBL/凝集素补体系统的新联系，MBL/凝集素补体系统负责在梗死心脏中募集大量CD45+髓样细胞（MF， GC和中性粒细胞）。我们怀疑这些炎症细胞是导致心室破裂、梗死边界区扩张和瘢痕以及心肌细胞萎缩的原因。此外，由于已知巨噬细胞表达和释放大量影响心肌细胞电压门控离子通道（Nav和Kv）功能的神经氨酸酶（也称为唾液酸酶），我们假设这些炎症细胞也负责梗死心脏中致命的心律失常。因此，我们将分析gp130-STAT3系统中心肌细胞特异性突变小鼠单核/巨噬细胞的募集、分化和分泌组是否发生改变，以及这种改变如何影响心肌梗死亚急性期和慢性期致死性心律失常的风险以及对适应性和非适应性重塑过程的影响。

Left ventricular remodeling induced by myocardial infarction (MI) contributes to and drives heart failure. Distinct changes in the pattern of circulating IL-6 type cytokines and alteration in myocardial gp130-receptor expression levels, activation status and associated downstream signaling cascades have been reported in patients with MI, cardiac hypertrophy and chronic heart failure. The signal transducer and activator of transcription 3 (STAT3), a major downstream mediator of the IL-6-gp130 signaling system, plays a key functional role in the heart with regard to angiogenesis, hypertrophy, inflammation, fibrosis and regeneration. In the acute phase after MI and during ischemia/reperfusion a strong activation of STAT3 is enhancing survival pathways in cardiomyocytes and lowers oxidative stress. In the later course of MI the intensity of gp130-mediated STAT3 activation is timely regulated and a moderate activation is critical for beneficial compensatory hypertrophy and angiogenesis. In turn, ongoing high and uncontrolled gp130-mediated STAT3 activation after MI promotes a continuously high degree of inflammation indicated by the presence of myeloid cells (macrophages, granulocytes, neutrophiles). As a driving force of STAT3-mediated post MI cardiac inflammation, we discovered a novel link to the MBL/Lectin complement system, which is responsible for recruiting high numbers of CD45+ myeloid cells (MF, GC and neutrophiles) in the infarcted heart. We suspect that these inflammatory cells are responsible for ventricular rupture and dilatation of the infarcts border zone and scar and for cardiomyocyte atrophy. In addition, since macrophages are known to express and release substantial levels of neuraminidases (also known as sialidases) that impact on the functionality of voltage-gated Ion channels (Nav and Kv) in cardiomyocytes, we hypothesize that these inflammatory cells are also responsible for fatal arrhythmias in infarcted hearts. Therefore, we will analyze whether the recruitment, the differentiation and the secretome of monocytes/macrophages are altered in mice with cardiomyocyte-specific mutations in the gp130-STAT3 system and how such alterations influence the risk for fatal arrhythmias and impact on adaptive and maladaptive remodeling processes in the sub-acute and chronic phase after MI.