Ischemia-induced STAT-1 Expression and Activation Play a Critical Role in Cardiomyocyte Apoptosis (original) (raw)
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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.
Journal of the American College of Cardiology, 2004
We have previously demonstrated that STAT-1 plays a critical role in promoting apoptotic cell death in cardiac myocytes following ischemia/reperfusion (I/R) injury. Epigallocatechin-3gallate (EGCG), the major constituent of green tea, has recently been reported to inhibit STAT-1 activity in noncardiac cells. In the present study, we have assessed the protective effects of EGCG and green tea extract (GTE) infusion on both cultures of cardiac myocytes and the isolated rat heart. EGCG reduced STAT-1 phosphorylation and protected cardiac myocytes against I/R-induced apoptotic cell death. Moreover, EGCG reduced the expression of a known STAT-1 pro-apoptotic target gene, Fas receptor. More interestingly, oral administration of GTE as well as EGCG infusion limited the extent of infarct size and attenuated the magnitude of myocyte apoptosis in the isolated rat heart exposed to I/R injury. This reduction cell death was associated with improved hemodynamic recovery and ventricular function in the ischemic/reperfused rat heart. This is the first report to show that consumption of green tea is able to mediate cardioprotection and enhance cardiac function during I/R injury. Because GTEmediated cardioprotection is achieved, at least in part, through inhibition of STAT-1 activity, we may postulate that a similar action can be implemented in the clinical setting to minimize STAT-1 activation levels in patients with acute coronary artery disease (CAD).
The FASEB Journal, 2004
We have previously demonstrated that STAT-1 plays a critical role in promoting apoptotic cell death in cardiac myocytes following ischemia/reperfusion (I/R) injury. Epigallocatechin-3gallate (EGCG), the major constituent of green tea, has recently been reported to inhibit STAT-1 activity in noncardiac cells. In the present study, we have assessed the protective effects of EGCG and green tea extract (GTE) infusion on both cultures of cardiac myocytes and the isolated rat heart. EGCG reduced STAT-1 phosphorylation and protected cardiac myocytes against I/R-induced apoptotic cell death. Moreover, EGCG reduced the expression of a known STAT-1 pro-apoptotic target gene, Fas receptor. More interestingly, oral administration of GTE as well as EGCG infusion limited the extent of infarct size and attenuated the magnitude of myocyte apoptosis in the isolated rat heart exposed to I/R injury. This reduction cell death was associated with improved hemodynamic recovery and ventricular function in the ischemic/reperfused rat heart. This is the first report to show that consumption of green tea is able to mediate cardioprotection and enhance cardiac function during I/R injury. Because GTEmediated cardioprotection is achieved, at least in part, through inhibition of STAT-1 activity, we may postulate that a similar action can be implemented in the clinical setting to minimize STAT-1 activation levels in patients with acute coronary artery disease (CAD).
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...
Role of STAT3 in Ischemic Preconditioning
Journal of Molecular and Cellular Cardiology, 2001
We recently demostrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 ) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPCinduced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium.
JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion
Circulation, 2001
Background-Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium. Methods and Results-We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 mol/L), an AT 1 blocker, or with tyrphostin AG490 (5 mol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium. Conclusions-These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function. (Circulation. 2001;104:325-329.)
STAT3 deletion sensitizes cells to oxidative stress
Biochemical and Biophysical Research Communications, 2009
The transcription factor STAT1 plays a role in promoting apoptotic cell death, whereas the related STAT3 transcription factor protects cardiac myocytes from ischemia/reperfusion (I/R) injury or oxidative stress. Cytokines belonging to the IL-6 family activate the JAK-STAT3 pathway, but also activate other cytoprotective pathways such as the MAPK-ERK or the PI3-AKT pathway. It is therefore unclear whether STAT3 is the only cytoprotective mediator against oxidative stressinduced cell death. Overexpression of STAT3 in primary neonatal rat ventricular myocytes (NRVM) protects against I/R-induced cell death. Moreover, a dominant negative STAT3 adenovirus (Ad ST3-DN) enhanced apoptotic cell death (81.2 ± 6.9%) compared to control infected NRVM (46.0 ± 3.1%) following I/R. Depletion of STAT3 sensitized cells to apoptotic cell death following oxidative stress. These results provide direct evidence for the role of STAT3 as a cytoprotective transcription factor in cells exposed to oxidative stress.
Role of the JAK–STAT Pathway in Protection Against Myocardial Ischemia/Reperfusion Injury
Trends in Cardiovascular Medicine, 2003
The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is a stress-responsive mechanism that transduces signals from the cell surface to the nucleus, thereby modulating gene expression. Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway. Although the functional consequences of this event remain to be elucidated, there is emerging evidence that JAK-STAT signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning. Specifically, brief episodes of myocardial ischemia/reperfusion activate JAK1 and JAK2, followed by recruitment of STAT1 and STAT3, resulting in transcriptional upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which then mediate the infarct-sparing effects of the late phase of preconditioning. The present review focuses on this novel cardioprotective role of JAK-STAT signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia/reperfusion injury. (Trends Cardiovasc Med 2003;13:72-79).
Intracellular function of interleukin-1 receptor antagonist in ischemic cardiomyocytes
Background: Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemiainduced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis.
STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7
Journal of Biological Chemistry, 2003
STAT1 (signal transducer and activator of transcription 1) has been implicated as a mediator of a variety of biological responses in response to stimulation by specific growth factors and cytokines. To understand better the role of STAT1 in the interferon-␥ (IFN-␥)-induced phenotype, we generated an active form of STAT1 (STAT1C) by substituting Cys residues for both Arg-656 and Asn-658 within the C-terminal loop of the STAT1 SH2 domain. The IFN-␥ activation site element was stimulated and bound efficiently by STAT1C without IFN-␥ treatment. STAT1C was found to be tyrosine-phosphorylated in the nucleus for more than 30 h after IFN-␥ stimulation. STAT1-negative U3A cells reexpressing STAT1C showed retarded cell growth and underwent apoptosis when treated with IFN-␥. Further analysis demonstrated that apoptosis was preceded by proteolytic cleavage of caspases 2, 3, and 7, and wild type STAT1 also induced cleavage of caspase 7 when expressed in STAT1-negative U3A cells, indicating that STAT1C augments potential activity of wild type STAT1. Studies with cycloheximide treatment showed that protein synthesis induced in the first 24 h after IFN-␥ treatment was required for apoptosis under these conditions. Finally, we found that STAT1C-induced apoptosis was, in part, mediated by caspase 2, 3, and 7 because benzyloxycarbonyl-valyl-aspartyl-valyl-alanyl-aspartic acid fluoromethyl ketone (Z-VDVAD-FMK) treatment partially blocked apoptosis. These results suggest that prolonged nuclear localization of activated STAT1 results in apoptosis involving specific regulation of caspase pathway.