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心力衰竭的重要因素。心肌梗死、心肌肥厚和慢性心力衰竭患者循环中IL-6型细胞因子的变化以及心肌gp130受体表达水平、激活状态和相关的下游信号转导通路的改变已有报道。信号转导和转录激活因子3(STAT3)是IL-6-gp130信号系统的主要下游调节因子，在心脏的血管生成、肥大、炎症、纤维化和再生等过程中发挥着重要的作用。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的激活强度被及时调节，适度的激活对有益的代偿性肥厚和血管生成至关重要。反过来，心肌梗死后持续的高和不受控制的gp130介导的STAT3激活促进了髓系细胞(巨噬细胞、粒细胞和中性粒细胞)的存在所指示的持续高度的炎症。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/Lectin补体系统的一个新的联系，该系统负责在梗塞心脏中招募大量的CD45髓系细胞(MF、GC和中性粒细胞)。我们怀疑这些炎性细胞是导致心肌梗塞边缘区域和疤痕的脑室破裂和扩张，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神经氨酸酶(也称为唾液酸酶)，影响心肌细胞电压门控离子通道(Nav和Kv)的功能，我们假设这些炎症细胞也与梗塞心脏的致命性心律失常有关。因此，我们将分析在心肌细胞特异性突变的gp130-STAT3系统中，单核/巨噬细胞的募集、分化和分泌体是否发生改变，以及这种改变如何影响心梗后亚急性期和慢性期发生致命性心律失常的风险以及对适应性和适应性不良重构过程的影响。

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.