Ischemia-induced STAT-1 Expression and Activation Play a Critical Role in Cardiomyocyte Apoptosis

Abstract

We show here that exposure of cardiac cells to simulated ischemia results in apoptosis and is accompanied by phosphorylation and increased expression and transcriptional activity of STAT-1. Similarly, interferon-␥, which is known to induce STAT-1 activation, also induced apoptosis in cardiac cells. STAT-1-transfected cells were more susceptible to ischemia-induced cell death than cells transfected with a control plasmid lacking the STAT-1 coding sequence. Furthermore, an antisense STAT-1 vector reduced both ischemia-and overexpressed STAT-1-induced cell death in cardiac cells. Both STAT-1 overexpression and interferon-␥ treatment or exposure to ischemia activated the promoter of the pro-apoptotic caspase-1 gene in cardiomyocytes. Finally, ischemia/reperfusion also induced STAT-1 activation and caspase-1 processing in ventricular myocytes in the intact heart ex vivo. Immunofluorescent staining demonstrated an increase in STAT-1-positive staining in cardiomyocytes in response to ischemia/reperfusion that co-localized with terminal deoxynucleotidyl transferase dVTP nick end-labeling-positive apoptotic cells. These results suggest that STAT-1 plays a critical role in the regulation of ischemia/reperfusion-induced apoptosis in cardiac cells, acting at least in part via a caspase-1 activation-dependent pathway.Loss of cardiomyocytes by programmed cell death (apoptosis) is an important mechanism in the development of cardiac failure during injury due to ischemia/reperfusion and myocardial infarction (1, 2). Recent studies have indicated that apoptotic death occurs in cardiac cells exposed to a variety of damaging stimuli both in vitro and in the intact heart in vivo (3-6). Thus, cardiac cells exposed to a hypoxic/ischemic insult followed by reperfusion undergo apoptotic cell death in vitro (3, 6). Similarly, apoptotic cell death is also observed in the intact heart following ischemia in vivo (4, 5). Despite the convincing evidence that apoptosis occurs, the mechanism and signaling pathway that leads to hypoxic/ischemic stimuli resulting in apoptosis in cardiac cells is as yet unknown. However, as in other cell types, caspases have been implicated in apoptotic cell death in cardiomyocytes (7). For example, the infarct size following ischemia/reperfusion of the intact heart in vivo can be reduced by priming animals with the nonspecific caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone, directly demonstrating the role of caspases in mediating cell death in cardiac cells (8).Cytokines and growth factors are known to modulate growth, differentiation, and death in many cell types. For example, interferons (IFNs) 1 have been shown to trigger cell cycle arrest and death in non-cardiac cells (9, 10), whereas many interleukins stimulate growth and protect cells from apoptosis (11, 12). These pro-and anti-apoptotic effects are mediated, at least in part, by signaling through a family of transcription factors called STATs. Six STATs have been cloned, some of which exist in different isomeric forms, and all shar...

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

“…Potential proapoptotic and significant prosurvival effects of STAT1 have been described previously (Shen et al, 2001;Stephanou and Latchman, 2003;Terui et al, 2004). Both effects were attributed to the ability of STAT1 to activate expression of either proapoptotic (Kumar et al, 1997;Stephanou et al, 2000Stephanou et al, , 2001 or prosurvival proteins (Stephanou et al, 1999;Madamanchi et al, 2001;Terui et al, 2004). We found here that in WT cells serine-phosphorylated STAT1 promotes cell survival through the regulation of expression of two known prosurvival genes, MCL-1 and HSP27 (Kabakov et al, 2003;Michels et al, 2005).…”

EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-γ: Role of JAK/STAT1 signaling and implications for HIV-associated dementia

“…state of inflammatory cytokine-mediated apoptotic signaling, leading to widespread neuron damage [12,16,22,23]. Pervious studies support a role for JAK/STAT activation in the mediation of neuronal damage in HAD [4] as well as stroke [26]. Given that green tea (-)-epigallocatechin-3-gallate (EGCG) can act to attenuate neuronal JAK/STAT-regulated neuronal damage [30], we wished whether EGCG could modulate HAD-like neuronal damage by inhibition of JAK1/STAT1 activation.…”

Induction of high STAT1 expression in transgenic mice with LQTS and heart failure

“…A trend of increased apoptosis in the absence of exposure to ischemia was also detected in cardiomyocytes transfected with a STAT1 construct compared to control cells transfected with the vector (Fig. 3A in Stephanou et al [25]). Because age-dependent apoptosis has been detected in TG-NS mouse hearts [16], we speculate that increased expression of STAT1 may be a cause for apoptosis in these mice.…”

“…Neonatal rat cardiomyocytes subjected to ischemia for 4 hours showed increased expression of STAT1, and cardiomyocytes transfected with STAT1 showed increased apoptosis with exposure to ischemia [25]. A trend of increased apoptosis in the absence of exposure to ischemia was also detected in cardiomyocytes transfected with a STAT1 construct compared to control cells transfected with the vector (Fig.…”

“…Neonatal rat cardiomyocytes subjected to ischemia for 4 hours showed increased expression of STAT1, and cardiomyocytes transfected with STAT1 showed increased apoptosis with exposure to ischemia [25]. A trend Wu et al…”