Melanie Hoch

Continuous Glycoprotein-130–Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction

Background— In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130Y757F mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. Methods and Results— The cardiomyocyte-restricted &agr;-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130Y757F mutant cardiomyocytes (&agr;MHC-Cretg/−;gp130fl/Y757F [Y757F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y757F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y757F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y757F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3flox/+) restricted to cardiomyocytes in Y757F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. Conclusion— Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.

STAT3 and cardiac remodeling

Multiple in vitro and in vivo studies showed that the signal transducer and activator of transcription 3 (STAT3) protein is involved in cardiomyocyte protection and hypertrophy and via paracrine pathways impacts on the non-myocyte compartment, i.e., the vasculature and the extracellular matrix. In this regard, STAT3 interacts with a broad range of cellular and molecular mechanisms that direct remodeling processes in cardiac physiology (exercise, pregnancy) and pathophysiology (pressure overload, ischemia/reperfusion, myocardial infarction, and cardiotoxic agents). STAT3 is constitutively activated by a multitude of factors including cytokines, growth factors, neurohormones, mechanical load, and ischemia. It acts as a signaling molecule, a transcription factor and according to latest observations as a mitochondrial protein involved in energy production. In this review, we provide an overview on STAT3 signaling and summarize the current understanding of the role of STAT3 for different aspects of cardiac remodeling obtained from numerous experimental and clinical studies. Finally, we highlight and critically discuss STAT3 signaling as a possible target for future therapeutic approaches in the setting of cardiac remodeling.

Erythropoietin Preserves the Endothelial Differentiation Capacity of Cardiac Progenitor Cells and Reduces Heart Failure during Anticancer Therapies

Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.

16-kDa Prolactin and Bromocriptine in Postpartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease emerging toward the end of pregnancy or in the first postpartal months in previously healthy women. Recent data suggest a central role of unbalanced peri-/postpartum oxidative stress that triggers the proteolytic cleavage of the nursing hormone prolactin (PRL) into a potent antiangiogenic, proapoptotic, and proinflammatory 16-kDa PRL fragment. This notion is supported by the observation that inhibition of PRL secretion by bromocriptine, a dopamine D2-receptor agonist, prevented the onset of disease in an animal model of PPCM and by first clinical experiences where bromocriptine seem to exert positive effects with respect to prevention or treatment of PPCM patients. Here, we highlight the current state of knowledge on diagnosis of PPCM, provide insights into the biology and pathophysiology of 16-kDa PRL and bromocriptine, and outline potential consequences for the clinical management and treatment options for PPCM patients.

STAT3 regulation of and by microRNAs in development and disease

MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs acting at the post-transcriptional level where they promote mRNA degradation and block protein translation. Recent findings suggest that complex transcriptional and post-transcriptional circuits control miRNAs. STAT3 has emerged as an important regulator of their expression and biogenesis and, in turn, STAT3 signaling pathways are controlled by distinct miRNAs. We summarize the current knowledge on STAT3 mediated processing of individual miRNAs and contrariwise, the modulation of the STAT3 pathway by miRNAs in development and in pathophysiological conditions such as immune processes, infection, cancer, cardiovascular disease and pulmonary hypertension.

Epo deficiency alters cardiac adaptation to chronic hypoxia.

The involvement of erythropoietin in cardiac adaptation to acute and chronic (CHx) hypoxia was investigated in erythropoietin deficient transgenic (Epo-TAg(h)) and wild-type (WT) mice. Left (LV) and right ventricular functions were assessed by echocardiography and hemodynamics. HIF-1α, VEGF and Epo pathways were explored through RT-PCR, ELISA, Western blot and immunocytochemistry. Epo gene and protein were expressed in cardiomyocytes of WT mice in normoxia and hypoxia. Increase in blood hemoglobin, angiogenesis and functional cardiac adaptation occurred in CHx in WT mice, allowing a normal oxygen delivery (O2T). Epo deficiency induced LV hypertrophy, increased cardiac output (CO) and angiogenesis, but O2T remained lower than in WT mice. In CHx Epo-TAg(h) mice, LV hypertrophy, CO and O2T decreased. HIF-1α and Epo receptor pathways were depressed, suggesting that Epo-TAg(h) mice could not adapt to CHx despite activation of cardioprotective pathways (increased P-STAT-5/STAT-5). HIF/Epo pathway is activated in the heart of WT mice in hypoxia. Chronic hypoxia induced cardiac adaptive responses that were altered with Epo deficiency, failing to maintain oxygen delivery to tissues.