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Stresses of a failing heart
Journal of Molecular and Cellular Cardiology 35 (2003) 1017–1019 www.elsevier.com/locate/yjmcc
Editorial
Stresses of a failing heart Despite the substantial progress that has been made during the past two decades of heart research, heart failure still remains a prominent cause of death in North America. A chronic increase in cardiac workload, such as may be imposed by valvular defects, uncontrolled hypertension, coronary artery disease, viral infection or myocardial infarction, is accompanied by distinct biochemical and neurohumoral adjustments. Following the initial insult a series of host responses become activated which lead to the production and liberation of bioactive factors including angiotensin-II, aldosterone, endothelin and inflammatory cytokines [1]. These act in a paracrine or autocrine fashion to reprogram the myocardium at the cellular and molecular levels [2]. In fact ventricular remodeling results in structural and functional changes to the myocardium that are initially adaptive and accommodate the impending contractile defect. However, in some patients for reasons unknown, these adaptive physiological processes eventually fail resulting in diminished ventricular performance and overt heart failure. Thus, heart failure represents a major financial and socioeconomic burden worldwide, since patients diagnosed with this form of heart disease require costly medical and long-term care. Although molecular mechanisms and signaling pathways responsible for heart failure are poorly defined, there is collective agreement that heart failure results from one or more mutually related events. In this regard, cellular and subcellular defects to key calcium-handling proteins of the sarcoplasmic reticulum [3,4], increased oxidative stress, from a reduced antioxidant reserve [5,6], mitochondrial damage, phenotypic alterations to myofibrillar [7,8] and extracellular matrix proteins [9] have been suggested to be part of the remodeling process that contribute to ventricular dysfunction and heart failure. Moreover, the limited ability of cardiac muscle itself for repair despite the recent detection of cardiac progenitor cells has significant consequence to patients who have suffered a heart attack or other forms of myocardial cell injury, since once heart cells become damaged they are readily disposed of either by an apoptotic or necrotic process [10,11]. Undoubtedly, the acute loss of working ventricular myocytes will impair contractility and ability of the heart to pump blood commensurate with the body’s needs resulting in heart failure. There is now considerable evidence to link aberrant myocyte cell death through apoptosis to heart failure. This has largely been substantiated by studies in which an increased apoptotic index was detected in the human failing left ventricle and various animals’ models of heart © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-2828(03)00239-6
failure [12–14]. Together these studies support the contention that excessive cell death through an apoptotic process may contribute to heart failure. Whether apoptosis is adaptive, maladaptive or contributes to ventricular remodeling and failure on an acute vs. chronic basis is less clear and remains an active area of inquiry. Though the pathways leading to ventricular failure are complex and likely involve more than one pathway, there is a growing body of clinical and experimental evidence to suggest that inflammatory cytokines, such as TNF$, may be involved and may underlie a number of host cell responses leading to molecular remodeling and contractile dysfunction. In fact, TNF$ has been associated with a number of disease entities including, viral myocarditis, allograft rejection, congestive heart failure and myocardial infraction (cf. Refs. [15,16]). Historically, the relationship between TNF$ and heart failure was first suggested and largely based on the astute and careful observations that common clinical symptoms were shared among patients with heart failure and chronic inflammatory disease [17]. The link between heart failure and TNF$ became even more compelling when increased circulating levels of TNF$ were identified in patients with overt heart failure [18,19]. It is now appreciated that increased production of TNF$ by the ventricular myocytes may contribute to contractile dysfunction and failure [1]. Indeed, TNF$ can reportedly, influence cardiac-gene expression and depress cardiac contractility [20]. Preliminary studies in our laboratory and others have demonstrated that cytokines and TNF$ can repress cardiac muscle-gene expression in isolated neonatal ventricular myocytes. Repression of cardiac-gene expression may contribute to the contractile defects associated with end-stage hypertrophy and heart failure. Moreover, systemic administrations of pathophysiological levels of TNF$ commonly seen in patients with heart failure impair left ventricular function largely through disruption of calcium homeostasis [21]. Perhaps, the most compelling evidence to link TNF$ to ventricular dysfunction is the recent generation of transgenic mice with cardiac-restricted expression of TNF$. These animals exhibit the typical sequale of dilated cardiomyopathy that recapitulates the human condition including poor exercise tolerance, diminished systolic and diastolic dysfunction and increased cell death [22]. The exact mechanism by which TNF$ depresses cardiac contractility is unknown. In this report by Ozcan et al., the authors characterize the functional and biochemical features of mitochondria of failing hearts
1018
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1017–1019
derived from transgenic mice expressing TNF$. Here, the authors report that mitochondria from TNF$-induced failing hearts displayed ultrastructural and functional abnormalities that were manifested by impaired oxidative phoshorylation, ATP production, reduced creatine kinase activity and mitochondrial DNA damage. Moreover, the authors demonstrated that mitochondria from failing hearts displayed an increased vulnerability to oxidative stress following anoxia–reoxygenation as evidenced by impaired calcium buffering and cytochrome c release. Collectively, the data provide evidence that mitochondrial defects associated with increased susceptibility to oxidative stress and impaired energy metabolism may underlie the contractile defects associated with heart failure. This mitochondrial defect could account for the contractile deficit associated with heart failure. The study further identifies that interventions to preserve mitochondrial function may improve left ventricular performance and prevent heart failure. While the study does provide some intriguing evidence to support the notion that increased susceptibility of mitochondria to oxidative stress may contribute to heart failure the overall conclusion reached must be interpreted with caution. While the authors conclude that mitochondria of failing TNF$-transgenic hearts are more vulnerable to oxidative stress injury, only one time point of failure was studied. Therefore, it is not clear whether the deterioration of mitochondrial function also coincides with the stage of failure or is an epiphenomenon of the event. Moreover, while the data are compelling, it is not clear whether the mitochondrial changes are due to the direct pleiotropic effects of TNF$ on mitochondrial-gene expression or adaptive changes from chronic-transgene expression. It is equivalently unknown whether the mitochondrial defects observed here are restricted to the context of TNF$-induced heart failure model utilized or are also present in other forms of heart failure, such as post-myocardial infarction, valvular defects or viral myocarditits. It must be stated that although TNF$-induced apoptosis has been suggested to be a causative factor of cardiac dysfunction leading to ventricular remodeling and end-stage heart failure; the ability of TNF$ to provoke apoptosis may not be a universally conserved feature of this cytokine. For example, there are now several reports indicating that TNF$ may be cytoprotective rather than cytotoxic [23]. This becomes an important aspect of the report since cytochrome c, a key player in the activation of the mitochondrial-death pathway leading to distal-caspase activation and apoptosis, is released by mitochondria following anoxia–reoxygenation. Since apoptosis was not monitored in this study, it is not clear whether the increased vulnerability of mitochondria to oxidative stress also reflected an increase incidence or susceptibility of the TNF$-induced failing hearts to apoptosis. It has recently been demonstrated that TNF$ alone was insufficient to trigger apoptosis of neonatal ventricular myocytes in the absence of the protein synthesis inhibitor cycloheximide [24,25]. This observation is consistent with other reports documenting the inability of TNF$ to trigger apopto-
sis in cell types other than cardiac mycoytes [26,27]. Interestingly, TNFR1 knockout mice were found to be more susceptible to apoptosis and ventricular dysfunction. Moreover, infarct size was found to be greater in the TNFR1 knockout mice compared to wild-type controls following myocardial infarction suggesting that TNF$-receptor activation may be important for preventing cell death [28]. However, a report by Krown et al. [29] demonstrated an increased incidence of apoptosis in adult ventricular myocytes following TNF$ stimulation. Whether TNF$ triggers cardiac cell apoptosis may instead depend on the developmental stage of failure, concentration or downstream signaling molecules that become activated. Alternatively, TNF$ may simultaneously activate both life- and death pathways in the heart with the relative activation of a given pathway ultimately determining whether the cell will live or die. The report by Ozcan et al. on page 1159 of this issue of the Journal of Molecular and Cellular Cardiology provides new insight into the biochemical basis of heart failure by identifying that mitochondria of failing hearts have an increased susceptibility to oxidative stress. The authors further conclude that this mitochondrial defect may be an underlying cause of ventricular dysfunction, leading to heart failure. The study suggests that therapeutic strategies designed to target this mitochondrial defect may be effective for improving cardiac function in patients with heart failure. References [1]
Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail 1996;2(3):243–9. [2] Schwartz K, Chassagne C, Boheler KR. The molecular biology of heart failure. J Am Coll Cardiol 1993;22(4 Suppl A):A30–3. [3] Afzal N, Dhalla NS. Differential changes in left and right ventricular SR calcium transport in congestive heart failure. Am J Physiol 1992; 262(3 Pt 2):H868–74. [4] Schwartz K, Carrier L, Lompre AM, Mercadier JJ, Boheler KR. Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene expression in the hypertrophied and failing heart. Basic Res Cardiol 1992;87(Suppl 1):285–90. [5] Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 1996;148(1):291–300. [6] Singal PK, Kirshenbaum LA. A relative deficit in antioxidant reserve may contribute in cardiac failure. Can J Cardiol 1990;6(2):47–9. [7] Mercadier JJ, Lompre AM, Swynghedauw B, Schwartz K. Plasticite du phenotype myocardique au cours de l’hypertrophie et de l’insuffisance cardiaques (Plasticity of myocardial phenotype during cardiac hypertrophy and failure). Bull Acad Natl Med 1993;177(6): 917–31. [8] Mercadier JJ, Lompre AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, et al. Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 1990;85(1):305–9. [9] Brilla CG, Rupp H. Myocardial collagen matrix remodeling and congestive heart failure. Cardiologia 1994;39(12 Suppl 1):389–93. [10] Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410(6829):701–5. [11] Anversa P. Myocyte apoptosis and heart failure [editorial]. Eur Heart J 1998;19(3):359–60.
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1017–1019 [12] Quaini F, Cigola E, Lagrasta C, Saccani G, Quaini E, Rossi C, et al. End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Circ Res 1994;75:1050–63. [13] Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, et al. Apoptosis in myocytes in end-stage heart failure [see comments]. New Engl J Med 1996;335(16):1182–9. [14] Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 2003;111(10):1497–504. [15] Mann DL, Young JB. Basic mechanisms in congestive heart failure. Recognizing the role of proinflammatory cytokines. Chest 1994;105(3):897–904. [16] Dibbs Z, Kurrelmeyer K, Kalra D, Seta Y, Wang F, Bozkurt B, et al. Cytokines in heart failure: pathogenetic mechanisms and potential treatment. Proc Assoc Am Physician 1999;111(5):423–8. [17] Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol 1998;274(3 Pt 2):R577–95. [18] Dibbs Z, Thornby J, White BG, Mann DL. Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials. J Am Coll Cardiol 1999; 33(7):1935–42. [19] Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. New Engl J Med 1990;323(4):236–41. [20] Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 1993;92(5): 2303–12. [21] Bozkurt B, Kribbs SB, Clubb Jr FJ, Michael LH, Didenko VV, Hornsby PJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97(14):1382–91. [22] Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81(4):627–35. [23] Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death [see comments]. Science 1996;274(5288):782–4.
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[24] Mustapha S, Kirshner A, de Moissac D, Kirshenbaum LA. A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes. Am J Physiol Heart Circ Physiol 2000;279(3): H939–45. [25] de Moissac D, Mustapha S, Greenberg AH, Kirshenbaum LA. Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha. J Biol Chem 1998;273(37):23946–51. [26] Beg AA, Baldwin Jr AS. Activation of multiple NF-kappa B/Rel DNA-binding complexes by tumor necrosis factor. Oncogene 1994; 9(5):1487–92. [27] Massaia M, Borrione P, Attisano C, Barral P, Beggiato E, Montacchini L, et al. Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients. Blood 1995;85(12):3679–87. [28] Kurrelmeyer KM, Michael LH, Baumgarten G, Taffet GE, Peschon JJ, Sivasubramanian N, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 2000;97(10):5456–61. [29] Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death J Clin Invest 1996;98(12):2854–65.
Lorrie A. Kirshenbaum* Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba, Room No. 3016, 351 Taché Avenue, Winnipeg, Man., Canada R2H 2A6 E-mail address: [email protected] (L.A. Kirshenbaum). Received and accepted 7 July 2003 * Tel.: +1-204-235-3661; fax: +1-204-233-6723.
Editorial
Stresses of a failing heart Despite the substantial progress that has been made during the past two decades of heart research, heart failure still remains a prominent cause of death in North America. A chronic increase in cardiac workload, such as may be imposed by valvular defects, uncontrolled hypertension, coronary artery disease, viral infection or myocardial infarction, is accompanied by distinct biochemical and neurohumoral adjustments. Following the initial insult a series of host responses become activated which lead to the production and liberation of bioactive factors including angiotensin-II, aldosterone, endothelin and inflammatory cytokines [1]. These act in a paracrine or autocrine fashion to reprogram the myocardium at the cellular and molecular levels [2]. In fact ventricular remodeling results in structural and functional changes to the myocardium that are initially adaptive and accommodate the impending contractile defect. However, in some patients for reasons unknown, these adaptive physiological processes eventually fail resulting in diminished ventricular performance and overt heart failure. Thus, heart failure represents a major financial and socioeconomic burden worldwide, since patients diagnosed with this form of heart disease require costly medical and long-term care. Although molecular mechanisms and signaling pathways responsible for heart failure are poorly defined, there is collective agreement that heart failure results from one or more mutually related events. In this regard, cellular and subcellular defects to key calcium-handling proteins of the sarcoplasmic reticulum [3,4], increased oxidative stress, from a reduced antioxidant reserve [5,6], mitochondrial damage, phenotypic alterations to myofibrillar [7,8] and extracellular matrix proteins [9] have been suggested to be part of the remodeling process that contribute to ventricular dysfunction and heart failure. Moreover, the limited ability of cardiac muscle itself for repair despite the recent detection of cardiac progenitor cells has significant consequence to patients who have suffered a heart attack or other forms of myocardial cell injury, since once heart cells become damaged they are readily disposed of either by an apoptotic or necrotic process [10,11]. Undoubtedly, the acute loss of working ventricular myocytes will impair contractility and ability of the heart to pump blood commensurate with the body’s needs resulting in heart failure. There is now considerable evidence to link aberrant myocyte cell death through apoptosis to heart failure. This has largely been substantiated by studies in which an increased apoptotic index was detected in the human failing left ventricle and various animals’ models of heart © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-2828(03)00239-6
failure [12–14]. Together these studies support the contention that excessive cell death through an apoptotic process may contribute to heart failure. Whether apoptosis is adaptive, maladaptive or contributes to ventricular remodeling and failure on an acute vs. chronic basis is less clear and remains an active area of inquiry. Though the pathways leading to ventricular failure are complex and likely involve more than one pathway, there is a growing body of clinical and experimental evidence to suggest that inflammatory cytokines, such as TNF$, may be involved and may underlie a number of host cell responses leading to molecular remodeling and contractile dysfunction. In fact, TNF$ has been associated with a number of disease entities including, viral myocarditis, allograft rejection, congestive heart failure and myocardial infraction (cf. Refs. [15,16]). Historically, the relationship between TNF$ and heart failure was first suggested and largely based on the astute and careful observations that common clinical symptoms were shared among patients with heart failure and chronic inflammatory disease [17]. The link between heart failure and TNF$ became even more compelling when increased circulating levels of TNF$ were identified in patients with overt heart failure [18,19]. It is now appreciated that increased production of TNF$ by the ventricular myocytes may contribute to contractile dysfunction and failure [1]. Indeed, TNF$ can reportedly, influence cardiac-gene expression and depress cardiac contractility [20]. Preliminary studies in our laboratory and others have demonstrated that cytokines and TNF$ can repress cardiac muscle-gene expression in isolated neonatal ventricular myocytes. Repression of cardiac-gene expression may contribute to the contractile defects associated with end-stage hypertrophy and heart failure. Moreover, systemic administrations of pathophysiological levels of TNF$ commonly seen in patients with heart failure impair left ventricular function largely through disruption of calcium homeostasis [21]. Perhaps, the most compelling evidence to link TNF$ to ventricular dysfunction is the recent generation of transgenic mice with cardiac-restricted expression of TNF$. These animals exhibit the typical sequale of dilated cardiomyopathy that recapitulates the human condition including poor exercise tolerance, diminished systolic and diastolic dysfunction and increased cell death [22]. The exact mechanism by which TNF$ depresses cardiac contractility is unknown. In this report by Ozcan et al., the authors characterize the functional and biochemical features of mitochondria of failing hearts
1018
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1017–1019
derived from transgenic mice expressing TNF$. Here, the authors report that mitochondria from TNF$-induced failing hearts displayed ultrastructural and functional abnormalities that were manifested by impaired oxidative phoshorylation, ATP production, reduced creatine kinase activity and mitochondrial DNA damage. Moreover, the authors demonstrated that mitochondria from failing hearts displayed an increased vulnerability to oxidative stress following anoxia–reoxygenation as evidenced by impaired calcium buffering and cytochrome c release. Collectively, the data provide evidence that mitochondrial defects associated with increased susceptibility to oxidative stress and impaired energy metabolism may underlie the contractile defects associated with heart failure. This mitochondrial defect could account for the contractile deficit associated with heart failure. The study further identifies that interventions to preserve mitochondrial function may improve left ventricular performance and prevent heart failure. While the study does provide some intriguing evidence to support the notion that increased susceptibility of mitochondria to oxidative stress may contribute to heart failure the overall conclusion reached must be interpreted with caution. While the authors conclude that mitochondria of failing TNF$-transgenic hearts are more vulnerable to oxidative stress injury, only one time point of failure was studied. Therefore, it is not clear whether the deterioration of mitochondrial function also coincides with the stage of failure or is an epiphenomenon of the event. Moreover, while the data are compelling, it is not clear whether the mitochondrial changes are due to the direct pleiotropic effects of TNF$ on mitochondrial-gene expression or adaptive changes from chronic-transgene expression. It is equivalently unknown whether the mitochondrial defects observed here are restricted to the context of TNF$-induced heart failure model utilized or are also present in other forms of heart failure, such as post-myocardial infarction, valvular defects or viral myocarditits. It must be stated that although TNF$-induced apoptosis has been suggested to be a causative factor of cardiac dysfunction leading to ventricular remodeling and end-stage heart failure; the ability of TNF$ to provoke apoptosis may not be a universally conserved feature of this cytokine. For example, there are now several reports indicating that TNF$ may be cytoprotective rather than cytotoxic [23]. This becomes an important aspect of the report since cytochrome c, a key player in the activation of the mitochondrial-death pathway leading to distal-caspase activation and apoptosis, is released by mitochondria following anoxia–reoxygenation. Since apoptosis was not monitored in this study, it is not clear whether the increased vulnerability of mitochondria to oxidative stress also reflected an increase incidence or susceptibility of the TNF$-induced failing hearts to apoptosis. It has recently been demonstrated that TNF$ alone was insufficient to trigger apoptosis of neonatal ventricular myocytes in the absence of the protein synthesis inhibitor cycloheximide [24,25]. This observation is consistent with other reports documenting the inability of TNF$ to trigger apopto-
sis in cell types other than cardiac mycoytes [26,27]. Interestingly, TNFR1 knockout mice were found to be more susceptible to apoptosis and ventricular dysfunction. Moreover, infarct size was found to be greater in the TNFR1 knockout mice compared to wild-type controls following myocardial infarction suggesting that TNF$-receptor activation may be important for preventing cell death [28]. However, a report by Krown et al. [29] demonstrated an increased incidence of apoptosis in adult ventricular myocytes following TNF$ stimulation. Whether TNF$ triggers cardiac cell apoptosis may instead depend on the developmental stage of failure, concentration or downstream signaling molecules that become activated. Alternatively, TNF$ may simultaneously activate both life- and death pathways in the heart with the relative activation of a given pathway ultimately determining whether the cell will live or die. The report by Ozcan et al. on page 1159 of this issue of the Journal of Molecular and Cellular Cardiology provides new insight into the biochemical basis of heart failure by identifying that mitochondria of failing hearts have an increased susceptibility to oxidative stress. The authors further conclude that this mitochondrial defect may be an underlying cause of ventricular dysfunction, leading to heart failure. The study suggests that therapeutic strategies designed to target this mitochondrial defect may be effective for improving cardiac function in patients with heart failure. References [1]
Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail 1996;2(3):243–9. [2] Schwartz K, Chassagne C, Boheler KR. The molecular biology of heart failure. J Am Coll Cardiol 1993;22(4 Suppl A):A30–3. [3] Afzal N, Dhalla NS. Differential changes in left and right ventricular SR calcium transport in congestive heart failure. Am J Physiol 1992; 262(3 Pt 2):H868–74. [4] Schwartz K, Carrier L, Lompre AM, Mercadier JJ, Boheler KR. Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene expression in the hypertrophied and failing heart. Basic Res Cardiol 1992;87(Suppl 1):285–90. [5] Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 1996;148(1):291–300. [6] Singal PK, Kirshenbaum LA. A relative deficit in antioxidant reserve may contribute in cardiac failure. Can J Cardiol 1990;6(2):47–9. [7] Mercadier JJ, Lompre AM, Swynghedauw B, Schwartz K. Plasticite du phenotype myocardique au cours de l’hypertrophie et de l’insuffisance cardiaques (Plasticity of myocardial phenotype during cardiac hypertrophy and failure). Bull Acad Natl Med 1993;177(6): 917–31. [8] Mercadier JJ, Lompre AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, et al. Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 1990;85(1):305–9. [9] Brilla CG, Rupp H. Myocardial collagen matrix remodeling and congestive heart failure. Cardiologia 1994;39(12 Suppl 1):389–93. [10] Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410(6829):701–5. [11] Anversa P. Myocyte apoptosis and heart failure [editorial]. Eur Heart J 1998;19(3):359–60.
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1017–1019 [12] Quaini F, Cigola E, Lagrasta C, Saccani G, Quaini E, Rossi C, et al. End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Circ Res 1994;75:1050–63. [13] Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, et al. Apoptosis in myocytes in end-stage heart failure [see comments]. New Engl J Med 1996;335(16):1182–9. [14] Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 2003;111(10):1497–504. [15] Mann DL, Young JB. Basic mechanisms in congestive heart failure. Recognizing the role of proinflammatory cytokines. Chest 1994;105(3):897–904. [16] Dibbs Z, Kurrelmeyer K, Kalra D, Seta Y, Wang F, Bozkurt B, et al. Cytokines in heart failure: pathogenetic mechanisms and potential treatment. Proc Assoc Am Physician 1999;111(5):423–8. [17] Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol 1998;274(3 Pt 2):R577–95. [18] Dibbs Z, Thornby J, White BG, Mann DL. Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials. J Am Coll Cardiol 1999; 33(7):1935–42. [19] Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. New Engl J Med 1990;323(4):236–41. [20] Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 1993;92(5): 2303–12. [21] Bozkurt B, Kribbs SB, Clubb Jr FJ, Michael LH, Didenko VV, Hornsby PJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97(14):1382–91. [22] Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81(4):627–35. [23] Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death [see comments]. Science 1996;274(5288):782–4.
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[24] Mustapha S, Kirshner A, de Moissac D, Kirshenbaum LA. A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes. Am J Physiol Heart Circ Physiol 2000;279(3): H939–45. [25] de Moissac D, Mustapha S, Greenberg AH, Kirshenbaum LA. Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha. J Biol Chem 1998;273(37):23946–51. [26] Beg AA, Baldwin Jr AS. Activation of multiple NF-kappa B/Rel DNA-binding complexes by tumor necrosis factor. Oncogene 1994; 9(5):1487–92. [27] Massaia M, Borrione P, Attisano C, Barral P, Beggiato E, Montacchini L, et al. Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients. Blood 1995;85(12):3679–87. [28] Kurrelmeyer KM, Michael LH, Baumgarten G, Taffet GE, Peschon JJ, Sivasubramanian N, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 2000;97(10):5456–61. [29] Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death J Clin Invest 1996;98(12):2854–65.
Lorrie A. Kirshenbaum* Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba, Room No. 3016, 351 Taché Avenue, Winnipeg, Man., Canada R2H 2A6 E-mail address: [email protected] (L.A. Kirshenbaum). Received and accepted 7 July 2003 * Tel.: +1-204-235-3661; fax: +1-204-233-6723.