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

心肌梗死后心脏受损的 gp130-STAT3 信号对骨髓细胞介导的炎症过程的影响

• 批准号: 223874705
• 负责人: Professorin Dr. Denise Hilfiker-Kleiner
• 金额: --
• 依托单位: Klinik für Innere Medizin, Schwerpunkt Kardiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/223874705?language=en
• 关键词: Effect; impaired; cardiac; gp130; STAT3

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.

由心肌梗死（MI）引起的左心室重构促成并驱动心力衰竭。在MI、心脏肥大和慢性心力衰竭患者中，循环IL-6型细胞因子的模式发生明显变化，心肌gp 130受体表达水平、激活状态和相关下游信号级联反应发生改变。信号转导和转录激活因子3（STAT 3）是IL-6-gp 130信号系统的主要下游介质，在心脏血管生成、肥大、炎症、纤维化和再生方面发挥关键功能作用。在MI后的急性期和缺血/再灌注期间，STAT 3的强烈激活增强了心肌细胞中的存活途径并降低了氧化应激。在MI的后期过程中，gp 130介导的STAT 3激活的强度被及时调节，并且适度的激活对于有益的代偿性肥大和血管生成是至关重要的。反过来，MI后gp 130介导的STAT 3活化持续升高且不受控制，促进了持续高度的炎症，表现为髓样细胞（巨噬细胞、粒细胞、嗜中性粒细胞）的存在。作为STAT 3介导的MI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，该系统负责在梗死心脏中招募大量的CD 45+骨髓细胞（MF，GC和嗜中性粒细胞）。我们怀疑这些炎性细胞是心室破裂、梗死边缘区和瘢痕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影响心肌细胞中电压门控离子通道（Nav和Kv）功能的神经氨酸酶（也称为唾液酸酶），因此我们假设这些炎性细胞也是梗死心脏中致命性心律失常的原因。因此，我们将分析是否招募，分化和单核细胞/巨噬细胞的分泌组在gp 130-STAT 3系统中的心肌细胞特异性突变的小鼠中发生改变，以及这些改变如何影响致命性心律失常的风险，并影响MI后亚急性和慢性阶段的适应性和适应不良重塑过程。