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

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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.