Key points are not available for this paper at this time.
Previously we reported that ischemia results in apoptosis and is accompanied by phosphorylation on Tyr-701 and increased expression and transcriptional activity of the signal transducer and activator of transcription-1 (STAT-1). In the present study, we show that exposure of cardiomyocytes to ischemia induced the phosphorylation of STAT-1 at another site, Ser-727. Moreover, STAT-1 is critical for the induction of Fas receptor and Fas ligand expression by ischemia/reperfusion (I/R). Transcriptional activation of Fas and FasL was dependent on Ser-727 of STAT-1 but was independent of Tyr-701. Similarly, Ser-727 but not Tyr-701 was required for enhancement of cardiomyocyte cell death by STAT-1 during I/R. In addition, inhibition of the p38 pathway prevented the induction and transcriptional activation of Fas and FasL in cardiac cells exposed to I/R, whereas inhibition of p42/p44 MAPK had no effect. Finally, I/R also induced phosphorylation of STAT-1 on Ser-727 and expression of Fas/FasL in ventricular myocytes in the intact heart ex vivo. These results indicate that Fas/FasL genes and apoptosis are activated by STAT-1 in cardiac myocytes exposed to I/R and these effects are dependent on the Ser-727 but not the Tyr-701 phosphorylation sites of STAT-1. Previously we reported that ischemia results in apoptosis and is accompanied by phosphorylation on Tyr-701 and increased expression and transcriptional activity of the signal transducer and activator of transcription-1 (STAT-1). In the present study, we show that exposure of cardiomyocytes to ischemia induced the phosphorylation of STAT-1 at another site, Ser-727. Moreover, STAT-1 is critical for the induction of Fas receptor and Fas ligand expression by ischemia/reperfusion (I/R). Transcriptional activation of Fas and FasL was dependent on Ser-727 of STAT-1 but was independent of Tyr-701. Similarly, Ser-727 but not Tyr-701 was required for enhancement of cardiomyocyte cell death by STAT-1 during I/R. In addition, inhibition of the p38 pathway prevented the induction and transcriptional activation of Fas and FasL in cardiac cells exposed to I/R, whereas inhibition of p42/p44 MAPK had no effect. Finally, I/R also induced phosphorylation of STAT-1 on Ser-727 and expression of Fas/FasL in ventricular myocytes in the intact heart ex vivo. These results indicate that Fas/FasL genes and apoptosis are activated by STAT-1 in cardiac myocytes exposed to I/R and these effects are dependent on the Ser-727 but not the Tyr-701 phosphorylation sites of STAT-1. signal transducer and activator of transcription interferon-γ Janus protein kinase mitogen-activated protein kinase Jun C-terminal protein kinase dominant-negative extracellular signal-regulated kinase ischemia/reperfusion Loss of cardiac myocytes by programmed cell death (apoptosis) is an important mechanism in the development of cardiac failure during injury due to ischemia/reperfusion and myocardial infarction (1Itoh G. Tamura J. Susuki Y. Koike M. Nomura M. Ito K. Am. J. Pathol. 1995; 146: 1325-1331PubMed Google Scholar, 2Fliss H. Gattinger D. Circ. Res. 1996; 79: 949-956Crossref PubMed Scopus (777) Google Scholar). 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 (3Umansky S.R. Cuenco G.M. Khutzian S.S. Barr P.J. Tomei L.D. Cell Death Differ. 1995; 2: 235-241PubMed Google Scholar, 4Cheng W. Kajstura J. Nitahara J.A. Li B. Reiss K. Liu Y. Clark W.A. Krajfwski S. Reed J.C. Olivetti G. Anversa P. Exp. Cell Res. 1996; 226: 316-327Crossref PubMed Scopus (317) Google Scholar, 5Gottlieb R.A. Burleson K.O. Kloner R.A. Babior B.M. Engler R.L. J. Clin. Invest. 1994; 94: 1621-1628Crossref PubMed Scopus (1357) Google Scholar, 6Narula J. Haider N. Virmani R. Di Salvo T.G. Kolodgie F.D. Hajjar R.J. Schmidt U. Semigran M.J. Dec W.G. Khaw B.A. N. Engl. J. Med. 1996; 335: 1182-1189Crossref PubMed Scopus (1246) Google Scholar). Thus, cardiac cells exposed to a hypoxic/ischemic insult followed by reperfusion undergo apoptotic cell death in vitro (3Umansky S.R. Cuenco G.M. Khutzian S.S. Barr P.J. Tomei L.D. Cell Death Differ. 1995; 2: 235-241PubMed Google Scholar, 6Narula J. Haider N. Virmani R. Di Salvo T.G. Kolodgie F.D. Hajjar R.J. Schmidt U. Semigran M.J. Dec W.G. Khaw B.A. N. Engl. J. Med. 1996; 335: 1182-1189Crossref PubMed Scopus (1246) Google Scholar). Similarly, apoptotic cell death is also observed in the intact heart following ischemia in vivo (4Cheng W. Kajstura J. Nitahara J.A. Li B. Reiss K. Liu Y. Clark W.A. Krajfwski S. Reed J.C. Olivetti G. Anversa P. Exp. Cell Res. 1996; 226: 316-327Crossref PubMed Scopus (317) Google Scholar, 5Gottlieb R.A. Burleson K.O. Kloner R.A. Babior B.M. Engler R.L. J. Clin. Invest. 1994; 94: 1621-1628Crossref PubMed Scopus (1357) Google Scholar). Despite the convincing evidence that apoptosis occurs, the mechanisms and signaling pathways which lead to apoptosis following hypoxic/ischemic stimuli in cardiac cells are as yet unknown. The Fas (CD95)/Fas ligand (CD95L) system is a key regulator of apoptosis. Fas, a 48-kDa transmembrane receptor glycoprotein, is a member of the tumor necrosis factor receptor superfamily of surface molecules (7Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4557) Google Scholar), and Fas expression is enhanced in cardiomyocytes exposed to hypoxia (8Tanaka M. Itoh H. Adachi S. Circ. Res. 1994; 75: 426-433Crossref PubMed Scopus (565) Google Scholar). The Fas ligand (FasL) which binds to the Fas receptor belongs to the tumor necrosis factor superfamily of cytokines and can exist as a membrane-bound or a soluble protein. Binding of Fas by its cognate ligand FasL mediates the recruitment of the Fas-associated death domain adapter molecule to the receptor complex. In turn, the upstream procaspase-8 is attracted to the complex and undergoes autoproteolytic activation (9Varfolomeev E.E. Schuchmann M. Luria V. Chiannilkulchai N. Beckmann J.S. Met I.L. Rebrikov D. Brodianski V.M. Kember O.C. Kollet O. Soffer D. Sobe T Avraham K.B. Goncharov H. Lonai P. Wallach D. Immunity. 1998; 2: 267-276Abstract Full Text Full Text PDF Scopus (1031) Google Scholar). This then leads to the activation of downstream caspases including caspase-3, followed by cleavage of key regulatory proteins resulting in apoptosis (9Varfolomeev E.E. Schuchmann M. Luria V. Chiannilkulchai N. Beckmann J.S. Met I.L. Rebrikov D. Brodianski V.M. Kember O.C. Kollet O. Soffer D. Sobe T Avraham K.B. Goncharov H. Lonai P. Wallach D. Immunity. 1998; 2: 267-276Abstract Full Text Full Text PDF Scopus (1031) Google Scholar). Cytokines and growth factors are known to modulate growth, survival, and death in many cell types. These pro- and anti-apoptotic effects are mediated, at least in part, by signaling through a family of transcription factors called signal transducers and activators of transcription (STATs).1 Six STATs have been cloned, some of which exist in different isomeric forms, and all share a high degree of conservation of their structural domains (10Horvath C.M. Darnell J.E. Curr. Opin. Cell Biol. 1997; 9: 233-239Crossref PubMed Scopus (177) Google Scholar, 11Ihle J. Cell. 1996; 84: 331-334Abstract Full Text Full Text PDF PubMed Scopus (1265) Google Scholar). These include a DNA-binding domain, a site for homo- or heterodimer formation and also conserved residues for tyrosine and serine phosphorylation by Janus protein kinases (JAKs) and mitogen-activated protein kinases (p42/44 and p38 MAPKs), respectively (12Zang X. Blenis J. Li H. Schindler C. Chen-Kiang S. Science. 1995; 267: 1894-1990Google Scholar, 13Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1414-1417Crossref Scopus (5025) Google Scholar). STATs phosphorylated by JAK/MAPK dimerize and translocate to the nucleus where they transactivate STAT responsive genes. Recent studies have implicated STATs in both pro- and anti-apoptotic signaling. For example, a STAT-1 deficient cell line is resistant to tumor necrosis factor α-induced apoptosis (14Kumar A. Commane M. Flickinger T.W. Horvath C.M. Stark G.R. Science. 1997; 278: 1630-1632Crossref PubMed Scopus (433) Google Scholar), and STAT-1 has been implicated in transcriptional activation of some caspases (15Chin Y.E. Kitagawa B. Kuida K. Flavell R.A. Fu X-Y. Mol. Cell. Biol. 1997; 17: 5328-5337Crossref PubMed Scopus (469) Google Scholar). In contrast, a dominant negative form of STAT-3 has been shown to prevent interleukin-6-dependent cell growth and induce apoptosis in a myeloid cell line (16Minami M. Inoue M. Wei S. Takeda M. Kishimoto T. Akira S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 3963-3966Crossref PubMed Scopus (312) Google Scholar). In addition, the ability of IFN α/β to rescue T cell clones from apoptosis induced by interleukin-2 withdrawal is dependent on STAT-2 (17Kaneko S. Suzuki N. Koizumi H. Yamamoto S. Sakane T. Clin. Exp. Immunol. 1997; 109: 165-193Google Scholar), and the anti-apoptotic effects of interleukin-9 appear to involve homo/hetero dimers of STAT-1, -3, and -5 (18Bauer J.H. Lui K.D. Lai S.Y. Goldsmith M.A. J. Biol. Chem. 1998; 273: 9255-9260Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Recently we have started to assess the role of STATs in mediating pro- and anti-apoptotic signals in the heart. For example, we have recently demonstrated that STAT-1 activation plays a critical role in inducing apoptosis in cardiac cells exposed to ischemia/reperfusion (I/R) in a caspase-1-dependent manner (19Stephanou A. Brar B. Knight R.A. Marber M.S. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: 10002-10008Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). In addition, we have shown that the phosphorylated active form of STAT-1 reduces the basal activity of the promoters of the anti-apoptotic genes, Bcl-2and Bcl-x, whereas STAT-3 increases promoter activity. Hence, STAT-1 and STAT-3 have opposing actions on the Bcl-2 and Bcl-x promoters (20Stephanou A. Brar B. Knight R.A. Latchman D.S. Cell Death Differ. 2000; 7: 329-330Crossref PubMed Scopus (151) Google Scholar). To extend these studies we have investigated the role of STAT-1 in regulating expression of Fas and Fas ligand during I/R of cardiac myocytes and in the intact perfused heart ex vivo. The STAT-1, STAT1-Ser-727 mutant (serine to alanine) and STAT1-Tyr-701 mutant (tyrosine to phenylalanine) expression vectors were kindly provided by Curt Horvath (Mount Sinai Medical Center, New York). The STAT-1 antisense vector was constructed by inserting the STAT-1 cDNA in the antisense orientation into the pcDNA3 vector. The dominant negative MKK6 construct was kindly provided by Eisuke Nishida (Kyoto including the Fas N. M. Y. N. T. Y. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google and FasL promoter were from a and upstream of the The Fas and FasL promoter to and to the transcription site as The of the FasL promoter The STAT-1 was constructed by a site from into of construct and expression vectors into cardiac as by the The cells was kindly provided by Kerr myocytes from the of that were were as A. Brar B. R. Knight R.A. Marber M.S. D. Latchman D.S. J. Mol. Cell 1998; Full Text PDF PubMed Scopus Google the following the cells were in of of on of the cell for to and the myocytes the to the cardiac cell was at a of cells This system cell that are myocytes as by a to were in cardiomyocytes following in and the were for The cells were then in in and the was by the at to as growth for an a of myocytes was To the cells to the growth of the cardiomyocyte was of and the cells were at in an for in an of In some cells exposed to ischemia for were to a for a or to In some cardiomyocytes were also for following the indicated The and the p38 MAPK were from New For the ex vivo were and in a and perfused an as M.S. Latchman D.S. Yellon 88: PubMed Scopus Google Scholar). The were exposed to of ischemia followed by of from the to the into which were for or in and in were exposed to a insult as and or following of were in of ventricular was in of then the was and the cells into were by of in of on was by and an of was to the which was for were then on a to and to and was as A. Knight R.A. A. Brar G. Latchman D.S. Yellon J. Immunol. PubMed Scopus Google Scholar). ventricular were in and and were then in and for followed by a or and or for a were in and were and by For the effects of STAT-1, or cell death in of expression vectors were by the of vector to the cells by the by of cells were following cells were in and to for activity. were also on the of apoptotic cells were by the of cells for both and as a of In all a of cells were cells STAT-1, or mutant were exposed to ischemia for and cells were in Cell were for a STAT-1 that as a site for STAT-1. were also a STAT-1 or STAT-3 for to the to the of the complex. results are as of at least independent were by was for was studies have demonstrated the enhanced expression and activation by phosphorylation on tyrosine the of the transcription factor STAT-1 in cardiomyocytes exposed to I/R (19Stephanou A. Brar B. Knight R.A. Marber M.S. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: 10002-10008Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). also that the factor was STAT-1 in the apoptosis of STAT-1 (19Stephanou A. Brar B. Knight R.A. Marber M.S. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: 10002-10008Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). In the present we apoptosis induced by I/R in cardiac myocytes also induced the phosphorylation of STAT-1 on serine the or p38 MAPK shown in cardiac myocytes exposed to ischemia enhanced STAT-1 Ser-727 phosphorylation as as STAT-1 enhanced expression and the of STAT-1 Ser-727 phosphorylation was increased following in STAT-1 Recently phosphorylation of STAT-1 at Ser-727 was shown to dependent on the activation of p38 MAPK J. PubMed Scopus Google Scholar, P. D. R. A. M. P. T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D. P. S. J.A. P. T. J. Immunol. Google Scholar). we also the of active phosphorylated MAPK in cardiomyocytes exposed to ischemia or I/R. shown in exposure of cardiomyocytes to ischemia enhanced phosphorylation of p38 the of MAPK to following I/R. The that the phosphorylation of p38 MAPK occurs as a and induction of Ser-727 is a and to ischemia and I/R. the observed in phosphorylation of p38 MAPK and STAT-1 Ser-727 in cardiomyocytes exposed to I/R in the of both Fas and of cardiomyocytes to I/R induced the expression of Fas and FasL The induction of Fas and FasL was not observed in cardiomyocytes exposed to ischemia a the required for induction of Fas and the p38 MAPK the enhancement of both Fas and FasL protein exposed to I/R. the p38 also the enhancement of STAT-1 Ser-727 phosphorylation The that both STAT-1 phosphorylation on Ser-727 and Fas/FasL are induced in cardiomyocytes exposed to I/R. Recently which results in STAT-1 Tyr-701 phosphorylation has been shown to modulate the protein of Fas and FasL in cells X. Fu J. Res. 1998; Google Scholar), that STAT-1 Fas/FasL in cardiac cells exposed to I/R. we studies to and FasL genes also at the of transcription by Fas and FasL promoter in cardiac cells exposed to or I/R. increased the activity of both the Fas and FasL promoters by and In addition, of STAT-1 enhanced the activity of Fas and FasL promoters by and respectively myocytes exposed to I/R also of the Fas and FasL promoters by and Moreover, of an antisense STAT-1 construct both the and activation of the Fas and FasL promoters These results indicate that the Fas and are genes for STAT-1. In the both the Fas and FasL promoters Recently has been demonstrated that phosphorylation of STAT-1 at Ser-727 by p38 MAPK is to modulate STAT-1 signaling pathways J. PubMed Scopus Google Scholar, P. D. R. A. M. P. T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D. P. S. J.A. P. T. J. Immunol. Google STAT-1 Ser-727 has been shown to a for both and p38 STAT-1 Tyr-701 is a for also demonstrated that STAT-1 enhanced the to cell death (19Stephanou A. Brar B. Knight R.A. Marber M.S. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: 10002-10008Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). in the present we the activity of STAT-1 in which Ser-727 had been to or Tyr-701 had been to for their ability to modulate the activity of the Fas and FasL of these was into cells and and cell to STAT-1 or STAT-1 phosphorylated on Ser-727 or Tyr-701. shown in the mutant was not phosphorylated on but was phosphorylated at whereas the mutant had the of phosphorylation we the Moreover, in results M. Stark G.R. J. Scopus Google Scholar), both the and the mutant of STAT-1 were to to in a from the cells In addition, was by an but not in from cells exposed to as STAT-1. of mutant the activation of both Fas and FasL promoters the STAT-1 in cardiac cells following exposure to or I/R. In contrast, mutant had a to STAT-1 in the promoters of both Fas and FasL and Thus, the and not phosphorylation site is important for mediating the enhancement of Fas and FasL promoter activity. This M.J. M.J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google in which the mutant as a dominant negative mutant on a promoter a STAT-1 responsive in was also the in the mutant the ability of STAT-1 to an promoter a site Hence, that the of different STAT-1 is different on different STAT-1 responsive genes. To the role of the p38 MAPK in pathway we in the or of dominant negative an upstream activator of p38 of p38 MAPK the of activation of Fas and FasL promoter activity in cardiac cells exposed to I/R of the of p38 also the activation of Fas and FasL promoter activity following I/R Recently the and p42/p44 MAPK have also been shown to modulate the expression of Fas and FasL in cells J. M. C. J. Exp. Med. 2000; PubMed Scopus Google Scholar, H. Y. M. Mol. Cell. Biol. Scopus Google Scholar). we the effects of and in of the Fas and FasL promoters in shown in of a dominant-negative the STAT-1 expression vector the of activation of both the Fas and FasL promoters in cardiac cells exposed to I/R. of STAT-1 a dominant-negative expression vector upstream activator of or of cardiac cells the in cardiac cells exposed to I/R had no on the activation of the Fas or FasL promoters following I/R These studies indicate that p38 and but not the are for STAT-1 activation of the Fas genes the phosphorylation at Ser-727 of STAT-1. have demonstrated that of STAT-1 induced apoptotic death in cardiac myocytes and of an antisense STAT-1 of cell death (19Stephanou A. Brar B. Knight R.A. Marber M.S. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: 10002-10008Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). we investigated the STAT-1 or can also modulate the of apoptotic death in cardiac myocytes following exposure to I/R. of or mutant enhanced the of apoptotic death in cardiac myocytes mutant in cardiac myocytes in of apoptotic cell death observed or the mutant Thus, these results that the and not phosphorylation site is critical not for mediating the enhancement of Fas and expression but also in apoptosis following exposure to cardiac cells to I/R. we vitro cardiac cells on Fas and FasL expression the induction of Ser-727 and MAPK were also in the intact heart. were to ischemia in the intact heart ex vivo in a exposure to ischemia the were for a The were then and to assess the of Fas, and shown in the of Fas, and FasL all increased following I/R in the intact whereas the of STAT-1 not also demonstrated an in Ser-727 in ventricular in to ischemia/reperfusion which was accompanied by an in the of and myocytes In addition, also demonstrated cardiomyocyte for STAT-1 Ser-727 in the nucleus and Fas in the was also FasL and STAT-1 Ser-727 not Thus, the increased of Fas and FasL during I/R the of the transcriptional activation of STAT-1 to the nucleus on both the Fas and FasL genes. Hence, these results a key role for STAT-1 in cell death in the intact heart by inducing the expression of Fas and of cardiac myocytes for Fas, and FasL in in a of for the STAT1-Ser-727 The Fas/FasL system plays an important role in the of in the In addition, the Fas/FasL system also in of apoptosis. For example, exposure of cardiomyocytes to hypoxia both Fas expression and cell death (8Tanaka M. Itoh H. Adachi S. Circ. Res. 1994; 75: 426-433Crossref PubMed Scopus (565) Google Scholar). from Fas in cell death following exposure to I/R C. A. H. J. P. 2000; PubMed Scopus Google Scholar). Thus, the Fas/FasL system is important in apoptosis in the heart following I/R. The mechanisms regulating apoptosis the Fas/FasL system have not yet been The present that exposure of cardiac myocytes to I/R in vitro and in the intact heart ex vivo results in the induction of Fas and FasL expression a of antisense STAT-1 vector in cardiac cells the enhancement of Fas and FasL promoter STAT-1 enhanced In turn, the which is not phosphorylated on the promoter activation and enhanced protein of Fas and whereas the mutant in the as STAT-1. Similarly, of STAT-1 or the mutant and not the mutant enhanced apoptotic cell death in cardiac also enhanced phosphorylation of both p38 MAPK and STAT-1 on Ser-727 and expression of Fas/FasL in the intact heart ex vivo exposed to I/R. This is by of activated STAT-1 increased Fas and FasL in cardiomyocytes in the intact heart exposed to I/R. Hence, these results that the phosphorylation site of STAT-1 is important in mediating cell death by a mechanism the induction of Fas and its cognate whereas tyrosine is not has been as critical for activation by STAT-1 and we that is the on a promoter a a that of site has no on the STAT-1 of genes as the induction of genes as M. Stark G.R. J. Scopus Google Scholar). results these that the of is promoter and can the Fas and FasL The transcriptional activity of STAT-1 phosphorylated on Ser-727 and Tyr-701 is that of STAT-1 phosphorylated on Tyr-701 studies have shown including to induce phosphorylation of STAT-1 on Ser-727 a p38 pathway in cells J. PubMed Scopus Google Scholar, P. D. R. A. M. P. T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D. P. S. J.A. P. T. J. Immunol. Google P. M. K. H. R. A. M. T. J. PubMed Scopus Google Scholar). In the present p38 activity to required for serine phosphorylation of STAT-1 in cardiac myocytes in to I/R. we show that the STAT-1 Ser-727 mutant is in Fas and FasL promoters in cardiac myocytes exposed to I/R, whereas the STAT-1 Tyr-701 mutant transcriptional activity. Hence, that in the Ser-727 phosphorylation of STAT-1 is also for by STAT-1. In cells the MAPK pathways by and p42/p44 have been implicated in the of Fas/FasL For example, withdrawal of factors leads to activation of pathway in cells resulting in FasL induction and cell death H. Y. M. Mol. Cell. Biol. Scopus Google Scholar). Similarly, of T cells to cell death results in both p38 and activation and is followed by the induction of FasL J. M. C. J. Exp. Med. 2000; PubMed Scopus Google Scholar). I/R injury to cardiac myocytes is p38 MAPK of the p38 pathway the of cardiomyocyte apoptosis in vitro and also in the intact heart ex vivo K. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Circ. Res. 2000; PubMed Scopus Google Scholar). In the present study, and inhibition of the p38 pathway Ser-727 phosphorylation of STAT-1 activation of the Fas and FasL that p38 MAPK activation is in STAT-1 Ser-727 phosphorylation and activation is also enhanced following ischemia and I/R A. Circ. Res. 2000; PubMed Scopus Google Scholar, A. Circ. Res. 1998; PubMed Scopus Google Scholar). of the pathway also the of cardiomyocyte apoptosis in vitro H. Li R.A. Cell Death Differ. PubMed Scopus Google Scholar). dominant-negative expression vector also Fas and FasL promoter activity. Thus, in to p38 also to the of Fas and FasL the activation of STAT-1. In contrast, to the effects in the heart of p38 and the MAPK family p42/p44 to in cardiac cell which as and are both in vitro and ex and these effects are by the p42/p44 pathway B. A. Knight R.A. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, and D. S. in Scholar). Moreover, in the heart exposed to I/R was increased by B. A. Knight R.A. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google and D. S. in Scholar). of p42/p44 in cardiac myocytes not the of cell that p42/p44 is not required for cell in B. A. Knight R.A. Yellon D. Latchman D.S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, and D. S. in Scholar). In the present but not the p42/p44 pathway Fas and FasL promoter activity. Hence, these studies present that the but not the p42/p44 pathway apoptosis in cardiac myocytes the of Fas and its cognate FasL which in is dependent on the phosphorylation of STAT-1 on Ser-727. injury and at least in by following I/R is an important of and The present on the of STAT-1 in the induction of cardiac apoptosis and the signaling pathways by which STAT-1 is activated during I/R in the heart as as the Fas and FasL genes as for STAT-1 in the heart. the mechanisms by which the apoptotic is in the heart lead to for
Stephanou et al. (Sun,) studied this question.