Many good reasons to have STAT3 in the heart (original) (raw)
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Proceedings of the National Academy of Sciences, 2003
Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor α in response to lipopolysaccharide than those with WT STAT3. Further...
Heart Failure Reviews, 2010
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.
STAT3, a key regulator of cell-to-cell communication in the heart
Cardiovascular Research, 2014
The signal transducer and activator of transcription 3 (STAT3) is fundamental for physiological homeostasis and stress-induced remodelling of the heart as deregulated STAT3 circuits are sufficient to induce dilated and peripartum cardiomyopathy and adverse remodelling after myocardial infarction. STAT3 activity depends on multiple post-translational modifications (phosphorylation, acetylation, and dimerization). It is regulated by multiple receptor systems, which are coupled to positive and negative feedback loops to ensure physiological and beneficial action. Its intracellular functions are diverse as it acts as a signalling protein, a transcription factor but also participates in mitochondria energy production and protection. STAT3 modulates proliferation, differentiation, survival, oxidative stress, and/or metabolism in cardiomyocytes, fibroblasts, endothelial cells, progenitor cells, and various inflammatory cells. By regulating the secretome of these cardiac cells, STAT3 influences a broad range of intercellular communication systems. It thereby impacts on the communication between cardiomyocytes, the plasticity of the cardiac microenvironment, the vasculature, the extracellular matrix, and the inflammation in response to physiological and pathophysiological stress. Here, we sum up current knowledge on STAT3-mediated intra-and intercellular communication within the heterogeneous cellular network of the myocardium to coordinate complex biological processes and discuss STAT3-dependent targets as novel therapeutic concepts to treat various forms of heart disease.
Effects of Cardiovascular Risk Factors on Cardiac STAT3
International Journal of Molecular Sciences
Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the diseas...
Potent selective inhibition of STAT 3 versus STAT 1 by cardiac hormones
Molecular and Cellular Biochemistry, 2012
Signal transducers and activators of transcription (STATs) are the final ''switches'' that activate gene expression patterns that lead to human malignancy. Extracellular signal-regulated kinases (ERK 1/2) activate STAT 3; four cardiovascular hormones inhibit ERK 1/2 kinases, leading to the hypothesis that they may also inhibit STATs. These four cardiac hormones, i.e., vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP), eliminate human cancers growing in mice. These four cardiac hormones' effects on STATs 1 and 3 were examined in human small-cell lung cancer and human pancreatic adenocarcinoma cells. Vessel dilator, LANP, kaliuretic peptide, and ANP maximally decreased STAT 3 by 88, 54, 55, and 65 %, respectively, at their 1 lM concentrations in human small-cell lung cancer cells and STAT 3 by 66, 57, 70, and 77 % in human pancreatic adenocarcinoma cells, respectively. The cardiac hormones (except LANP) also significantly decreased STAT 3 measured by Western blots. These cardiac hormones did not decrease STAT 1 in either human small-cell lung cancer or pancreatic adenocarcinoma cells. We conclude that these four cardiac hormones are significant inhibitors of STAT 3, but not STAT 1, in human small-cell lung cancer and pancreatic adenocarcinoma cells, which suggests a specificity for these hormones' anticancer mechanism(s) of action enzymology in human cancer cells.
Cardiovascular research, 2003
The signal transduction pathways mediating the progression to failure have been intensively studied in a variety of in vitro and in vivo animal models. Recently, acute activation of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) has been observed in the heart, but whether this is sustained in ischemic heart disease (IHD) or dilated cardiomyopathy (DCM) has not been previously addressed. We assessed the tyrosine phosphorylation of STAT1, 3, 5 and 6 in ventricular samples of explanted human hearts with IHD (n=11) and DCM (n=9) as an indication of STAT activation. Samples from normal donor hearts (n=9) acted as controls. In parallel, we also assessed protein expression and phosphorylation of three major families of mitogen-activated protein kinases (MAPKs); ERK, p38 MAPK and c-Jun NH(2)-terminal kinase (JNK). All STAT isoforms were significantly phosphorylated in DCM. In contrast, only the phosphorylation of STATs 1 and 5 were significantly enha...
The FASEB Journal, 2002
We have demonstrated previously that the STAT-1 transcription factor plays a key role in ischemia/reperfusion (I/R)-induced apoptosis in cardiac myocytes. In the present study we assessed which region of the STAT-1 molecule mediates apoptosis in cardiac myocytes. A STAT-1 construct (amino acid 350-750) lacking the N-terminus could enhance I/R-induced apoptosis in cardiac myocytes. However, a STAT-1 construct, which lacks 60 amino acids at the C-terminus (amino acid 691-750), was ineffective in promoting I/R-induced apoptosis in cardiac myocytes. Furthermore, overexpression of a C-terminal STAT-1 construct (amino acid 691-750) containing the transcriptional activation domain, but not the DNA binding domain, strongly enhanced I/R-induced apoptotic cell death. Cardiac myocytes isolated from mice expressing a truncated C-terminal STAT-1 were more sensitive to I/R-induced cell death. Finally, isolated hearts from these animals exposed to I/R injury had larger infarct size and greater number of TUNEL-positive myocytes than control hearts. These studies demonstrate that the C-terminal transactivation domain of STAT-1 is necessary and sufficient for I/R injury-induced apoptosis in cardiac myocytes.