Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Abstract

Cardiac fibroblasts play an essential role in the physiology of the heart. These produce extracellular matrix proteins and synthesize angiogenic and cardioprotective factors. Although fibroblasts of cardiac origin are known to be resistant to apoptosis and to remain metabolically active in situations compromising cell survival, the underlying mechanisms are unknown. Here, we report that cardiac fibroblasts were more resistant than dermal or pulmonary fibroblasts to mitochondria-dependent cell death. Cytochrome c release was blocked in cardiac fibroblasts but not in dermal fibroblasts treated with staurosporine, etoposide, serum deprivation, or simulated ischemia, precluding caspase-3 activation and DNA fragmentation. Resistance to apoptosis of cardiac fibroblasts correlated with the expression of the anti-apoptotic protein Bcl-2, whereas skin and lung fibroblasts did not express detectable levels of this protein. Bcl-xL, Bax, and Bak were expressed at similar levels in cardiac, dermal, and lung fibroblasts. In addition, the death of cardiac fibroblasts during hypoxia was not associated with the cleavage of Bid but rather with Bcl-2 disappearance, suggesting the requirement of the mitochondrial apoptotic machinery to execute death receptor-induced programmed cell death. Knockdown of bcl-2 expression by siRNA in cardiac fibroblasts increased their apoptotic response to staurosporine, serum, and glucose deprivation and to simulated ischemia. Moreover, dermal fibroblasts overexpressing Bcl-2 achieved a similar level of resistance to these stimuli as cardiac fibroblasts. Thus, our data demonstrate that Bcl-2 is an important effector of heart fibroblast resistance to apoptosis and highlight a probable mechanism for promoting survival advantage in fibroblasts of cardiac origin. Cardiac fibroblasts play an essential role in the physiology of the heart. These produce extracellular matrix proteins and synthesize angiogenic and cardioprotective factors. Although fibroblasts of cardiac origin are known to be resistant to apoptosis and to remain metabolically active in situations compromising cell survival, the underlying mechanisms are unknown. Here, we report that cardiac fibroblasts were more resistant than dermal or pulmonary fibroblasts to mitochondria-dependent cell death. Cytochrome c release was blocked in cardiac fibroblasts but not in dermal fibroblasts treated with staurosporine, etoposide, serum deprivation, or simulated ischemia, precluding caspase-3 activation and DNA fragmentation. Resistance to apoptosis of cardiac fibroblasts correlated with the expression of the anti-apoptotic protein Bcl-2, whereas skin and lung fibroblasts did not express detectable levels of this protein. Bcl-xL, Bax, and Bak were expressed at similar levels in cardiac, dermal, and lung fibroblasts. In addition, the death of cardiac fibroblasts during hypoxia was not associated with the cleavage of Bid but rather with Bcl-2 disappearance, suggesting the requirement of the mitochondrial apoptotic machinery to execute death receptor-induced programmed cell death. Knockdown of bcl-2 expression by siRNA in cardiac fibroblasts increased their apoptotic response to staurosporine, serum, and glucose deprivation and to simulated ischemia. Moreover, dermal fibroblasts overexpressing Bcl-2 achieved a similar level of resistance to these stimuli as cardiac fibroblasts. Thus, our data demonstrate that Bcl-2 is an important effector of heart fibroblast resistance to apoptosis and highlight a probable mechanism for promoting survival advantage in fibroblasts of cardiac origin. Programmed cell death (PCD) 1The abbreviations used are: PCD, programmed cell death; COXIV, cytochrome c oxidase subunit IV; ECM, extracellular matrix; EYFP, enhanced yellow fluorescent protein; MEF, mouse embryonic fibroblast; PFA, paraformaldehyde; siRNA, small interfering RNA; STS, staurosporine; z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone; PBS, phosphate-buffered saline; SD, serum deprivation; RT, reverse transcriptase; SDGD, serum and glucose deprivation. 1The abbreviations used are: PCD, programmed cell death; COXIV, cytochrome c oxidase subunit IV; ECM, extracellular matrix; EYFP, enhanced yellow fluorescent protein; MEF, mouse embryonic fibroblast; PFA, paraformaldehyde; siRNA, small interfering RNA; STS, staurosporine; z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone; PBS, phosphate-buffered saline; SD, serum deprivation; RT, reverse transcriptase; SDGD, serum and glucose deprivation. is involved in heart morphogenesis during embryonic development (1van den Hoff M.J.B. van den Eijnde S.M. 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Indeed, fibroblasts of cardiac origin were more resistant than and fibroblasts to etoposide, serum deprivation, and simulated ischemia. the mechanisms data to the of cytochrome c as the mechanism of cardiac fibroblast resistance to cardiac fibroblasts expressed an detectable level of the anti-apoptotic protein Bcl-2, which is in cell development Am. J. Google Scholar), including dermal L. P. J.J. J. 1997; 45: PubMed Scopus Google and lung R.J. Am. J. Cell Mol. Biol. 1999; 20: PubMed Scopus Google fibroblasts. Here, we the that the of Bcl-2 expression in cardiac fibroblasts their resistance to mitochondria-dependent Cell and cardiac fibroblasts the heart of of the with cells were in and for in with serum and was to cardiomyocytes that did not to the and these were with Cardiac fibroblasts were to was and and lung fibroblasts were by of skin and the used to the heart fibroblasts. and lung fibroblasts were in serum and used or the of the were and was used at was to the at the and described in the the at serum and glucose deprivation, cells were in and in glucose and was by cells in deprivation a in a of and the to a and at for the in the of Cell of cell death was by the at the of are expressed as of cell death in treated at the of the was as of cells or with Cell death and apoptosis for were in and the of DNA was by as reported (14Sanchis D. Mayorga M. Ballester M. Comella J.X. Cell Death Differ. 2003; 10: 977-986Crossref PubMed Scopus (59) Google Scholar). of were at the of the by cells in a and were for and to a as reported C. M. J. Comella J.X. J. 2002; PubMed Scopus Google Scholar). of the were by of as a of the and cytochrome oxidase subunit as a for mitochondrial are of and the of the cells were the and with in cell were and the was used as protein cell was in and by the was and protein was to and with relevant were to and with the or the of cytochrome c and cells were in and were with with PBS, and as described (14Sanchis D. Mayorga M. Ballester M. Comella J.X. Cell Death Differ. 2003; 10: 977-986Crossref PubMed Scopus (59) Google Scholar). cell were with for at were with and in used in this caspase-3 Cell Bak Cell Apaf-1 Bid mouse Bcl-2 subunit at cytochrome c cytochrome c at and were at at and were and at of and of was with the to cardiac and dermal fibroblasts, the of were reverse and The of Bcl-2 was by the and which a of The was and was in a and and the was were in and by of was as the for in the X. M. J. Comella J.X. J. 1999; PubMed Google Scholar). Bcl-2 and Bcl-2 was in C. M. J. Comella J.X. J. 2002; PubMed Scopus Google Scholar). fibroblasts were by at and in of with of or of yellow fluorescent protein Cardiac fibroblasts were at with of by of or the of In the expression was by the were treated with at a of or serum deprivation, for were by in with and with an was as the of cells or fragmentation. are the of in Bcl-2 were by and by and in to the Bcl-2 small interfering and or the and In to the of the siRNA in Bcl-2 were by embryonic fibroblasts of of cells were by and in of the of and cells were for the expression of Bcl-2 and by of or were with of by in cardiac or dermal fibroblasts at in a of of were in and in for the of the as described in the was to was in the by cells with by and cells were for were expressed as of cells with cells in the were with and fibroblasts. was used to the the response of cardiac and fibroblasts for as well as to the in the of fibroblasts. was Cardiac but or to Programmed Cell death was in cardiac, dermal and pulmonary fibroblasts to stimuli known to the etoposide, which DNA T. V. K.A. 2001; PubMed Scopus Google the T. V. K.A. 2001; PubMed Scopus Google Scholar), and serum deprivation K. Y. E. Wang X. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Cell death by of exposure to etoposide, STS, and serum deprivation, was more than in pulmonary and dermal fibroblasts than in cardiac fibroblasts The of the of exposure to for fibroblast that cardiac fibroblasts were than dermal fibroblasts in a of known to a of other cell by was also in fibroblasts the in and mouse embryonic fibroblasts in Indeed, cell death was in and data not that STS, etoposide, and serum deprivation cell death mainly by mitochondria-dependent apoptosis in fibroblasts, as has been reported T. V. K.A. 2001; PubMed Scopus Google Scholar). These that fibroblasts of cardiac origin were more resistant than skin and lung fibroblasts to apoptotic cell death by the mitochondrial Cardiac DNA and resistance of cardiac fibroblasts to apoptosis was by of the of and serum deprivation did not caspase-3 in cardiac fibroblasts but the activation of the of caspase-3 in skin fibroblasts of DNA cardiac and dermal fibroblasts treated with or serum deprivation the of DNA in cardiac fibroblasts, whereas was in DNA of dermal fibroblasts and The role of in DNA by and serum deprivation was by the that DNA was in dermal fibroblasts with and data not These that cardiac fibroblasts caspase-dependent apoptosis the in Cardiac Cytochrome c the molecular involved in cardiac fibroblast relative resistance to caspase-dependent we the of cytochrome c and in and of cytochrome c and to the in dermal fibroblasts but not in cardiac fibroblasts The release of mitochondria correlated with the activation of caspase-3 and These that cardiac fibroblast resistance to apoptosis occurs of cytochrome c Cardiac than to by to a ischemia. In to a in which the the of also to a in and such as the response of cardiac and dermal fibroblasts to such an it has been described that cardiac fibroblasts have a capacity to heart at for a Am. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), and in by apoptosis G. M. Hayakawa Y. J. M. A. Y. S. Fujiwara T. Fujiwara H. Circ. Res. 1998; PubMed Scopus Google Scholar). In our of serum and glucose deprivation dermal fibroblasts apoptosis of and in dermal fibroblasts was correlated with the of the cytochrome c and Cardiac fibroblasts to of simulated and caspase-3 activation was These data that cardiac resistance to apoptosis mechanisms of cytochrome c Bcl-2 in Cardiac but in or proteins the of in and and are the known of apoptotic cytochrome c release S. 2002; Scholar). The of anti-apoptotic of the Bcl-2 such as Bcl-2 and Bcl-xL, cytochrome c release by a mechanism involving Bcl-2 and in the of anti-apoptotic Bcl-2 proteins are by of Bcl-2 known as proteins P. A. J. Cell Sci. 2002; PubMed Google Scholar). by and of the Bcl-2 protein Bid is for the activation of cytochrome c release of the death X. H. C. Wang X. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). we the expression of proteins in protein cardiac, and dermal fibroblasts. of proteins was with to the of the several against these proteins are not J. Cell Biol. 2002; PubMed Scopus Google Scholar). Thus, we against and Bak not and we against Bcl-xL, and Bcl-2 in to the J. Cell Biol. 2002; PubMed Scopus Google Scholar). proteins Bid and Bcl-2 and and anti-apoptotic were expressed at similar levels in cardiac, and dermal fibroblasts proteins and which of the mitochondrial release of cytochrome were also expressed in fibroblast cell Bcl-2 was in protein of pulmonary and dermal fibroblasts whereas cardiac fibroblasts expressed detectable of this protein were several being the of in Bcl-2 in cardiac fibroblasts or Bcl-2 in dermal and pulmonary fibroblasts by Bcl-2 expression in of fibroblasts not In an to the of Bcl-2 expression in dermal fibroblasts at the or we Bcl-2 detectable levels of Bcl-2 in dermal fibroblasts whereas in cardiac fibroblasts, the Bcl-2 was suggesting that bcl-2 expression is in fibroblasts at the expression of Bcl-2 in fibroblasts of cardiac origin that it a role the resistance of these cells against Resistance of Cardiac to with Bcl-2 but with or of expression was in heart fibroblasts during with and and serum deprivation and was not in dermal fibroblasts by whereas anti-apoptotic and Bak and were expressed at similar levels of cell and proteins and of the Bcl-2 P. A. J. Cell Sci. 2002; PubMed Google Scholar). to apoptotic stimuli by their expression by such as cleavage or P. A. J. Cell Sci. 2002; PubMed Google Scholar). expression of protein which are for apoptosis in other cell such as J. Cell Biol. 2002; PubMed Scopus Google Scholar), did not with caspase-3 activation in fibroblasts did not to our are and levels of this protein in J. Cell Biol. 2002; PubMed Scopus Google and data not In addition, the resistance of cardiac fibroblasts to simulated Bcl-2 expression was apoptosis was in these cells of hypoxia and did not with Bid cleavage but rather with the of Bcl-2 these data demonstrate to dermal and pulmonary fibroblasts, cardiac fibroblasts Bcl-2 expression in and that activation of apoptosis with a in Bcl-2 expression rather than with or of other of Bcl-2 in the Resistance of Cardiac to at for the role of Bcl-2 expression in the resistance of cardiac fibroblasts to a Bcl-2 silencing for several by the siRNA at the was synthesized by a and the in reverse This and reverse were and the by fibroblasts are at by cells a with in addition, did not Thus, in to the of the Bcl-2 siRNA in Bcl-2 we to the embryonic fibroblast cell as described under the of the siRNA in Bcl-2 but not the was we of cardiac and dermal fibroblasts. Bcl-2 silencing a apoptotic in cardiac cells treated with STS, serum, and glucose deprivation or simulated ischemia, whereas it dermal fibroblasts, as These data a role of Bcl-2 in and of apoptosis were than in with This be by a of cells by the of in apoptotic the role of Bcl-2 in the resistance of heart fibroblasts to dermal fibroblasts with a for Bcl-2 C. M. J. Comella J.X. J. 2002; PubMed Scopus Google were more resistant to and serum and glucose deprivation than cells with in dermal fibroblasts apoptosis to similar to in cardiac fibroblasts, which express Bcl-2 in dermal fibroblasts Bcl-2 in cardiac of in cardiac fibroblasts apoptosis Bcl-2 expression and STS, the data that apoptosis occurs the mitochondrial in fibroblasts and to Bcl-2 as the for cardiac fibroblast resistance to programmed cell death. Cardiac the cardiac a comprising of and A.M. and Scholar). heart but to heart of the of function of cardiomyocytes and a of ECM, which tissue B. 1999; PubMed Scopus Google Scholar). heart cardiac fibroblasts and secrete ECM that the space left by dead The increased of cardiac fibroblasts, during stress situations promoting death of other cell types, the development of resistance mechanisms against cell death. The a for the molecular mechanisms underlying the resistance of cardiac fibroblasts to PCD, and at in to cardiac fibroblast cell death. report that cardiac fibroblasts are more resistant than fibroblasts of other dermal and pulmonary fibroblasts, to cell by stimuli with STS, etoposide, serum deprivation, and simulated cell death at a in fibroblasts of cardiac origin than in dermal fibroblasts. The resistance of for the proteins and which are essential for mitochondrial and T. V. K.A. 2001; PubMed Scopus Google Scholar), the relevant role of the cytochrome in these The of the is that apoptotic cytochrome c release is blocked in cardiac but not dermal fibroblasts, to a mechanism of resistance to that not cell but cell origin or level of of cytochrome c release correlated with expression of Bcl-2 but not of and other Bcl-2 which were expressed in of fibroblasts. also that Bid is in cardiac and dermal fibroblasts during simulated of This that mitochondria the of death in fibroblasts by this death cardiac fibroblasts are against a of death our data resistance of cardiac fibroblasts to glucose and serum deprivation a report the of DNA of hypoxia (24Long X. Boluyt M. Hipolito M.L. Lundberg M.S. Zheng J.S. O'Neill L. Cirielli C. Lakatta E.G. Crow M.T. J. Clin. Investig. 1997; 99: 2635-2643Crossref PubMed Scopus (270) Google Scholar). These are of cardiac fibroblasts play an important role in the of the the in is by a in serum and glucose of Bcl-2 was as the of M. U. S. P. J. PubMed Scopus Google and was to a survival S. Nature. PubMed Scopus Google Scholar). Although the mechanisms by which Bcl-2 cell survival are still a matter of debate S. 2002; Scholar), of cytochrome c J. X. K. A.M. J. D.P. Wang X. 1997; PubMed Scopus Google Scholar). This that expression of Bcl-2 in fibroblasts of cardiac origin is involved in the of cytochrome c release and in resistance against of expression in cardiac fibroblasts is Bcl-2 is in and to cells the and cells such as M. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In bcl-2 is expressed in cell of the skin during embryonic but is in skin cells but the L. P. J.J. J. 1997; 45: PubMed Scopus Google Scholar). of Bcl-2 expression in dermal fibroblasts of the Bcl-2 as Bcl-2 was in these In addition, fibroblasts also Bcl-2 It is in with by that pulmonary fibroblasts Bcl-2 expression during lung R.J. Am. J. Cell Mol. Biol. 1999; 20: PubMed Scopus Google Scholar). our data to Bcl-2 as a relevant of cardiac fibroblast resistance to hypoxia are with or of Bcl-2 has been involved in the resistance of other cell types, mainly to hypoxia S. Y. H. H. Y. Nature. PubMed Scopus Google Scholar). of Bcl-2 in the fibroblast cell has been to proliferation during by apoptosis by this F. X. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). Here, we also in of a role of Bcl-2 in the of cytochrome c release and enhanced survival of cardiac fibroblasts. of Bcl-2 expression increased apoptosis in cardiac but not in dermal fibroblasts during serum and glucose deprivation, or simulated ischemia. expression of Bcl-2 in dermal fibroblasts resistance to and and apoptosis at the level as in cardiac fibroblasts. of in cardiac fibroblasts the anti-apoptotic of Bcl-2, that cardiac fibroblasts are able to apoptosis are Although it is the of the it is to the role of Bcl-2 as cell cycle in cardiac fibroblasts. Indeed, Bcl-2 cell cycle by a mechanism involving increased expression of the and the protein G. J. A. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). This of Bcl-2 in cell cycle is of under as has been associated with In we for the of a anti-apoptotic mechanism in cardiac, but not in dermal or pulmonary fibroblasts, which the of Bcl-2 expression and cytochrome c and the This anti-apoptotic mechanism be involved in the resistance of cardiac fibroblasts to cell death during heart these cells to remain active other cell are our data Bcl-2 as a cardiac fibroblast survival the role of cardiac fibroblasts in scar and heart J. for the mouse embryonic fibroblasts and for the fibroblast cell also for the