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Piero Anversa - One of the best experts on this subject based on the ideXlab platform.
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A matter of life and death: cardiac myocyte apoptosis and regeneration
The Journal of clinical investigation, 2003Co-Authors: Bernardo Nadal-ginard, Jan Kajstura, Piero Anversa, Annarosa LeriAbstract:Of late, life has become more complicated in cardiovascular biology. Life was simpler when the prevalent dogma stating that the heart is a terminally differentiated organ without regenerative capacity remained unchallenged (1). This static view of the myocardium implied that both myocyte death and myocyte replication played no meaningful role in cardiac homeostasis and could be safely ignored. In the absence of myocyte renewal, cell death by apoptosis or necrosis had to be extremely low or non-existent to explain the preservation of the cardiac mass throughout the lifespan of the individual. Even very low rates of myocyte death would have resulted in the complete disappearance of the myocardium in a few decades. Thus, it is not surprising that the existence of myocyte apoptosis remained controversial during the past decade (2). Recent findings indicating the presence in the adult myocardium of a cell population with the behavior and potential of cardiac stem cells has challenged the status quo, provided an explanation for the existence of a subpopulation of immature cycling Myocytes and embraced myocyte death and myocyte renewal as the two sides of the proverbial coin of cardiac homeostasis (3). This myocyte renewal depends on the differentiation of primitive cells into immature Myocytes that might divide two to four times before becoming terminally differentiated and permanently withdrawn from the cell cycle. There is no evidence that already mature cardioMyocytes can de-differentiate, re-enter the cell cycle, and proliferate. In this new light, the presence, regulation, and physiological consequences of myocyte apoptosis have gained new significance. Two papers in this issue of the JCI highlight the effect of this type of myocyte death in cardiac performance and provide new insights on the role of myocyte death and renewal in cardiovascular physiology (4, 5).
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Myocyte proliferation and ventricular remodeling
Journal of Cardiac Failure, 2002Co-Authors: Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:Improvement in the methodological approach to the analysis of the myocardium has provided clear evidence of cardiac myocyte proliferation, questioning the general belief that the growth of the adult heart under physiological and pathological conditions can occur only by cellular hypertrophy. Myocyte regeneration contributes via myocyte death to the physiological turnover of Myocytes and via myocyte hypertrophy to cardiac remodeling. Several questions, however, remain to be answered. Among them, it is still unknown whether myocyte multiplication exerts a positive and/or negative effect on ventricular anatomy and cardiac function. The addition of newly generated Myocytes leads to cavitary dilation with relative thinning of the wall. Conversely, myocyte proliferation, characterized by the parallel addition of cells, can be expected to increase wall thickness, decrease chamber size, and ameliorate cardiac performance.
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Myocyte Growth and Cardiac Repair
Journal of Molecular and Cellular Cardiology, 2002Co-Authors: Piero Anversa, Annarosa Leri, Jan Kajstura, Bernardo Nadal-ginardAbstract:Abstract Introduced several decades ago, the dogma persists that ventricular Myocytes are terminally differentiated cells and cardiac repair by myocyte regeneration is completely inhibited shortly after birth. On the basis that cardiac Myocytes are unable to divide in the adult heart, myocyte growth under physiologic and pathologic conditions is believed to be restricted to cellular hypertrophy. Evidence is presented to indicate that this old paradigm has to be changed to include myocyte replication as a significant component of the cellular processes of ventricular remodeling. Importantly, myocyte death, apoptotic and necrotic in nature, has to be regarded as an additional critical variable of the multifactorial events implicated in the alterations of cardiac anatomy and myocardial structure of the decompensated heart. Methodologies are currently available to recognize and measure quantitatively the contribution of myocyte size, number and death to the adaptation of the overloaded heart and its progression to cardiac failure.
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myocyte proliferation in end stage cardiac failure in humans
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Jan Kajstura, Annarosa Leri, Nicoletta Finato, Carla Di Loreto, Carlo Alberto Beltrami, Piero AnversaAbstract:Introduced several decades ago, the dogma persists that cardiac Myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in Myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that Myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 Myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 Myocytes per million) and in idiopathic dilated cardiomyopathy (131 Myocytes per million). Because the left ventricle contains 5.8 × 109 Myocytes, these mitotic indices imply that 81.2 × 103, 882 × 103, and 760 × 103 Myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of Myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in Myocytes was obtained, providing unequivocal proof of myocyte proliferation.
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myocyte proliferation in end stage cardiac failure in humans
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Jan Kajstura, Annarosa Leri, Nicoletta Finato, Carla Di Loreto, Carlo Alberto Beltrami, Piero AnversaAbstract:Introduced several decades ago, the dogma persists that cardiac Myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in Myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that Myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 Myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 Myocytes per million) and in idiopathic dilated cardiomyopathy (131 Myocytes per million). Because the left ventricle contains 5.8 × 109 Myocytes, these mitotic indices imply that 81.2 × 103, 882 × 103, and 760 × 103 Myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of Myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in Myocytes was obtained, providing unequivocal proof of myocyte proliferation.
Jan Kajstura - One of the best experts on this subject based on the ideXlab platform.
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A matter of life and death: cardiac myocyte apoptosis and regeneration
The Journal of clinical investigation, 2003Co-Authors: Bernardo Nadal-ginard, Jan Kajstura, Piero Anversa, Annarosa LeriAbstract:Of late, life has become more complicated in cardiovascular biology. Life was simpler when the prevalent dogma stating that the heart is a terminally differentiated organ without regenerative capacity remained unchallenged (1). This static view of the myocardium implied that both myocyte death and myocyte replication played no meaningful role in cardiac homeostasis and could be safely ignored. In the absence of myocyte renewal, cell death by apoptosis or necrosis had to be extremely low or non-existent to explain the preservation of the cardiac mass throughout the lifespan of the individual. Even very low rates of myocyte death would have resulted in the complete disappearance of the myocardium in a few decades. Thus, it is not surprising that the existence of myocyte apoptosis remained controversial during the past decade (2). Recent findings indicating the presence in the adult myocardium of a cell population with the behavior and potential of cardiac stem cells has challenged the status quo, provided an explanation for the existence of a subpopulation of immature cycling Myocytes and embraced myocyte death and myocyte renewal as the two sides of the proverbial coin of cardiac homeostasis (3). This myocyte renewal depends on the differentiation of primitive cells into immature Myocytes that might divide two to four times before becoming terminally differentiated and permanently withdrawn from the cell cycle. There is no evidence that already mature cardioMyocytes can de-differentiate, re-enter the cell cycle, and proliferate. In this new light, the presence, regulation, and physiological consequences of myocyte apoptosis have gained new significance. Two papers in this issue of the JCI highlight the effect of this type of myocyte death in cardiac performance and provide new insights on the role of myocyte death and renewal in cardiovascular physiology (4, 5).
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Myocyte proliferation and ventricular remodeling
Journal of Cardiac Failure, 2002Co-Authors: Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:Improvement in the methodological approach to the analysis of the myocardium has provided clear evidence of cardiac myocyte proliferation, questioning the general belief that the growth of the adult heart under physiological and pathological conditions can occur only by cellular hypertrophy. Myocyte regeneration contributes via myocyte death to the physiological turnover of Myocytes and via myocyte hypertrophy to cardiac remodeling. Several questions, however, remain to be answered. Among them, it is still unknown whether myocyte multiplication exerts a positive and/or negative effect on ventricular anatomy and cardiac function. The addition of newly generated Myocytes leads to cavitary dilation with relative thinning of the wall. Conversely, myocyte proliferation, characterized by the parallel addition of cells, can be expected to increase wall thickness, decrease chamber size, and ameliorate cardiac performance.
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Myocyte Growth and Cardiac Repair
Journal of Molecular and Cellular Cardiology, 2002Co-Authors: Piero Anversa, Annarosa Leri, Jan Kajstura, Bernardo Nadal-ginardAbstract:Abstract Introduced several decades ago, the dogma persists that ventricular Myocytes are terminally differentiated cells and cardiac repair by myocyte regeneration is completely inhibited shortly after birth. On the basis that cardiac Myocytes are unable to divide in the adult heart, myocyte growth under physiologic and pathologic conditions is believed to be restricted to cellular hypertrophy. Evidence is presented to indicate that this old paradigm has to be changed to include myocyte replication as a significant component of the cellular processes of ventricular remodeling. Importantly, myocyte death, apoptotic and necrotic in nature, has to be regarded as an additional critical variable of the multifactorial events implicated in the alterations of cardiac anatomy and myocardial structure of the decompensated heart. Methodologies are currently available to recognize and measure quantitatively the contribution of myocyte size, number and death to the adaptation of the overloaded heart and its progression to cardiac failure.
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evidence that human cardiac Myocytes divide after myocardial infarction
The New England Journal of Medicine, 2001Co-Authors: Antonio Paolo Beltrami, Jan Kajstura, Annarosa Leri, Nicoletta Finato, Rossana Bussani, Konrad Urbanek, Shaomin Yan, Bernardo Nadalginard, F Silvestri, Carlo Alberto BeltramiAbstract:Background The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of Myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of Myocytes in the adult heart. Therefore, we studied the extent of mitosis among Myocytes after myocardial infarction in humans. Methods Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile ri...
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myocyte proliferation in end stage cardiac failure in humans
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Jan Kajstura, Annarosa Leri, Nicoletta Finato, Carla Di Loreto, Carlo Alberto Beltrami, Piero AnversaAbstract:Introduced several decades ago, the dogma persists that cardiac Myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in Myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that Myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 Myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 Myocytes per million) and in idiopathic dilated cardiomyopathy (131 Myocytes per million). Because the left ventricle contains 5.8 × 109 Myocytes, these mitotic indices imply that 81.2 × 103, 882 × 103, and 760 × 103 Myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of Myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in Myocytes was obtained, providing unequivocal proof of myocyte proliferation.
Annarosa Leri - One of the best experts on this subject based on the ideXlab platform.
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A matter of life and death: cardiac myocyte apoptosis and regeneration
The Journal of clinical investigation, 2003Co-Authors: Bernardo Nadal-ginard, Jan Kajstura, Piero Anversa, Annarosa LeriAbstract:Of late, life has become more complicated in cardiovascular biology. Life was simpler when the prevalent dogma stating that the heart is a terminally differentiated organ without regenerative capacity remained unchallenged (1). This static view of the myocardium implied that both myocyte death and myocyte replication played no meaningful role in cardiac homeostasis and could be safely ignored. In the absence of myocyte renewal, cell death by apoptosis or necrosis had to be extremely low or non-existent to explain the preservation of the cardiac mass throughout the lifespan of the individual. Even very low rates of myocyte death would have resulted in the complete disappearance of the myocardium in a few decades. Thus, it is not surprising that the existence of myocyte apoptosis remained controversial during the past decade (2). Recent findings indicating the presence in the adult myocardium of a cell population with the behavior and potential of cardiac stem cells has challenged the status quo, provided an explanation for the existence of a subpopulation of immature cycling Myocytes and embraced myocyte death and myocyte renewal as the two sides of the proverbial coin of cardiac homeostasis (3). This myocyte renewal depends on the differentiation of primitive cells into immature Myocytes that might divide two to four times before becoming terminally differentiated and permanently withdrawn from the cell cycle. There is no evidence that already mature cardioMyocytes can de-differentiate, re-enter the cell cycle, and proliferate. In this new light, the presence, regulation, and physiological consequences of myocyte apoptosis have gained new significance. Two papers in this issue of the JCI highlight the effect of this type of myocyte death in cardiac performance and provide new insights on the role of myocyte death and renewal in cardiovascular physiology (4, 5).
-
Myocyte proliferation and ventricular remodeling
Journal of Cardiac Failure, 2002Co-Authors: Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:Improvement in the methodological approach to the analysis of the myocardium has provided clear evidence of cardiac myocyte proliferation, questioning the general belief that the growth of the adult heart under physiological and pathological conditions can occur only by cellular hypertrophy. Myocyte regeneration contributes via myocyte death to the physiological turnover of Myocytes and via myocyte hypertrophy to cardiac remodeling. Several questions, however, remain to be answered. Among them, it is still unknown whether myocyte multiplication exerts a positive and/or negative effect on ventricular anatomy and cardiac function. The addition of newly generated Myocytes leads to cavitary dilation with relative thinning of the wall. Conversely, myocyte proliferation, characterized by the parallel addition of cells, can be expected to increase wall thickness, decrease chamber size, and ameliorate cardiac performance.
-
Myocyte Growth and Cardiac Repair
Journal of Molecular and Cellular Cardiology, 2002Co-Authors: Piero Anversa, Annarosa Leri, Jan Kajstura, Bernardo Nadal-ginardAbstract:Abstract Introduced several decades ago, the dogma persists that ventricular Myocytes are terminally differentiated cells and cardiac repair by myocyte regeneration is completely inhibited shortly after birth. On the basis that cardiac Myocytes are unable to divide in the adult heart, myocyte growth under physiologic and pathologic conditions is believed to be restricted to cellular hypertrophy. Evidence is presented to indicate that this old paradigm has to be changed to include myocyte replication as a significant component of the cellular processes of ventricular remodeling. Importantly, myocyte death, apoptotic and necrotic in nature, has to be regarded as an additional critical variable of the multifactorial events implicated in the alterations of cardiac anatomy and myocardial structure of the decompensated heart. Methodologies are currently available to recognize and measure quantitatively the contribution of myocyte size, number and death to the adaptation of the overloaded heart and its progression to cardiac failure.
-
evidence that human cardiac Myocytes divide after myocardial infarction
The New England Journal of Medicine, 2001Co-Authors: Antonio Paolo Beltrami, Jan Kajstura, Annarosa Leri, Nicoletta Finato, Rossana Bussani, Konrad Urbanek, Shaomin Yan, Bernardo Nadalginard, F Silvestri, Carlo Alberto BeltramiAbstract:Background The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of Myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of Myocytes in the adult heart. Therefore, we studied the extent of mitosis among Myocytes after myocardial infarction in humans. Methods Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile ri...
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myocyte proliferation in end stage cardiac failure in humans
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Jan Kajstura, Annarosa Leri, Nicoletta Finato, Carla Di Loreto, Carlo Alberto Beltrami, Piero AnversaAbstract:Introduced several decades ago, the dogma persists that cardiac Myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in Myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that Myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 Myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 Myocytes per million) and in idiopathic dilated cardiomyopathy (131 Myocytes per million). Because the left ventricle contains 5.8 × 109 Myocytes, these mitotic indices imply that 81.2 × 103, 882 × 103, and 760 × 103 Myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of Myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in Myocytes was obtained, providing unequivocal proof of myocyte proliferation.
Krishna Singh - One of the best experts on this subject based on the ideXlab platform.
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reactive oxygen species mediate amplitude dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac Myocytes
Circulation Research, 2001Co-Authors: David R Pimentel, Deborah A Siwik, Lei Xiao, Jay K Amin, Thomas A Miller, Jason Viereck, Jennifer Oliverkrasinski, Ragavendra R Baliga, Jing Wang, Krishna SinghAbstract:Oxidative stress stimulates both growth and apoptosis in cardiac Myocytes in vitro. We investigated whether oxidative stress mediates hypertrophy and apoptosis in cyclically stretched ventricular Myocytes. Neonatal rat ventricular Myocytes cultured on laminin-coated silastic membranes were stretched cyclically (1 Hz) at low (nominal 5%) and high (nominal 25%) amplitudes for 24 hours. Stretch caused a graded increase in superoxide anion production as assessed by superoxide dismutase (SOD)-inhibitable cytochrome c reduction or electron paramagnetic resonance spectroscopy. The role of reactive oxygen species (ROS) was assessed using the cell-permeable SOD/catalase mimetics Mn(II/III)tetrakis(1-methyl-4-peridyl) (MnTMPyP) and EUK-8. Stretch-induced increases in protein synthesis ( 3 H-leucine incorporation) and cellular protein content were completely inhibited by MnTMPyP (0.05 mmol/L) at both low and high amplitudes of stretch. In contrast, while MnTMPyP inhibited basal atrial natriuretic factor (ANF) mRNA expression, the stretch-induced increase in ANF mRNA expression was not inhibited by MnTMPyP. In contrast to hypertrophy, only high-amplitude stretch increased myocyte apoptosis, as reflected by increased DNA fragmentation on gel electrophoresis and an ≈3-fold increase in the number of TUNEL-positive Myocytes. Similarly, only high-amplitude stretch increased the expression of bax mRNA. Myocyte apoptosis and bax expression stimulated by high-amplitude stretch were inhibited by MnTMPyP. Both low- and high-amplitude stretch caused rapid phosphorylation of ERK1/2, while high-, but not low-, amplitude stretch caused phosphorylation of JNKs. Activation of both ERK1/2 and JNKs was ROS-dependent. Thus, cyclic strain causes an amplitude-related increase in ROS, associated with differential activation of kinases and induction of hypertrophic and apoptotic phenotypes.
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Adrenergic regulation of cardiac myocyte apoptosis.
Journal of cellular physiology, 2001Co-Authors: Krishna Singh, Douglas B. Sawyer, Lei Xiao, Andrea Remondino, Wilson S ColucciAbstract:The direct effects of catecholamines on cardiac Myocytes may contribute to both normal physiologic adaptation and pathologic remodeling, and may be associated with cellular hypertrophy, apoptosis, and alterations in contractile function. Norepinephrine (NE) signals via alpha- and beta-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac Myocytes in vitro demonstrate that stimulation of beta1-AR induces apoptosis which is cAMP-dependent and involves the voltage-dependent calcium influx channel. In contrast, stimulation of beta2-AR exerts an anti-apoptotic effect which appears to be mediated by a pertussis toxin-sensitive G protein. Stimulation of alpha1-AR causes myocyte hypertrophy and may exert an anti-apoptotic action. In transgenic mice, myocardial overexpression of either beta1-AR or G(alpha)s is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Myocardial overexpression of beta2-AR at low levels results in improved cardiac function, whereas expression at high levels leads to dilated cardiomyopathy. Overexpression of wildtype alpha1B-AR does not result in apoptosis, whereas overexpression of G(alpha)q results in myocyte hypertrophy and/or apoptosis depending on the level of expression. Differential activation of the members of the mitogen-activated protein kinase (MAPK) superfamily and production of reactive oxygen species appear to play a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and hypertrophy. This review summarizes current knowledge about the molecular and cellular mechanisms involved in the regulation of cardiac myocyte apoptosis via stimulation of adrenergic receptors and their coupled effector pathways.
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inhibition of copper zinc superoxide dismutase induces cell growth hypertrophic phenotype and apoptosis in neonatal rat cardiac Myocytes in vitro
Circulation Research, 1999Co-Authors: Deborah A Siwik, Douglas B. Sawyer, John D Tzortzis, David R Pimental, Donny L F Chang, Patrick J Pagano, Krishna Singh, Wilson S ColucciAbstract:Abstract—Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that inhibition of endogenous antioxidant enzymes can regulate the phenotype of cardiac Myocytes. Neonatal rat ventricular Myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited SOD activity and increased intracellular superoxide in a concentration-dependent manner. A low concentration (1 μmol/L) of DDC stimulated myocyte growth, as demonstrated by increases in protein synthesis, cellular protein, prepro–atrial natriuretic peptide, and c-fos mRNAs and decreased sarcoplasmic reticulum Ca2+ATPase mRNA. These actions were all inhibited by the superoxide scavenger Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC (100 μmol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering, characteristic nuclear morphology, in situ terminal deoxynucleotidyl trans...
Wilson S Colucci - One of the best experts on this subject based on the ideXlab platform.
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Adrenergic regulation of cardiac myocyte apoptosis.
Journal of cellular physiology, 2001Co-Authors: Krishna Singh, Douglas B. Sawyer, Lei Xiao, Andrea Remondino, Wilson S ColucciAbstract:The direct effects of catecholamines on cardiac Myocytes may contribute to both normal physiologic adaptation and pathologic remodeling, and may be associated with cellular hypertrophy, apoptosis, and alterations in contractile function. Norepinephrine (NE) signals via alpha- and beta-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac Myocytes in vitro demonstrate that stimulation of beta1-AR induces apoptosis which is cAMP-dependent and involves the voltage-dependent calcium influx channel. In contrast, stimulation of beta2-AR exerts an anti-apoptotic effect which appears to be mediated by a pertussis toxin-sensitive G protein. Stimulation of alpha1-AR causes myocyte hypertrophy and may exert an anti-apoptotic action. In transgenic mice, myocardial overexpression of either beta1-AR or G(alpha)s is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Myocardial overexpression of beta2-AR at low levels results in improved cardiac function, whereas expression at high levels leads to dilated cardiomyopathy. Overexpression of wildtype alpha1B-AR does not result in apoptosis, whereas overexpression of G(alpha)q results in myocyte hypertrophy and/or apoptosis depending on the level of expression. Differential activation of the members of the mitogen-activated protein kinase (MAPK) superfamily and production of reactive oxygen species appear to play a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and hypertrophy. This review summarizes current knowledge about the molecular and cellular mechanisms involved in the regulation of cardiac myocyte apoptosis via stimulation of adrenergic receptors and their coupled effector pathways.
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inhibition of copper zinc superoxide dismutase induces cell growth hypertrophic phenotype and apoptosis in neonatal rat cardiac Myocytes in vitro
Circulation Research, 1999Co-Authors: Deborah A Siwik, Douglas B. Sawyer, John D Tzortzis, David R Pimental, Donny L F Chang, Patrick J Pagano, Krishna Singh, Wilson S ColucciAbstract:Abstract—Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that inhibition of endogenous antioxidant enzymes can regulate the phenotype of cardiac Myocytes. Neonatal rat ventricular Myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited SOD activity and increased intracellular superoxide in a concentration-dependent manner. A low concentration (1 μmol/L) of DDC stimulated myocyte growth, as demonstrated by increases in protein synthesis, cellular protein, prepro–atrial natriuretic peptide, and c-fos mRNAs and decreased sarcoplasmic reticulum Ca2+ATPase mRNA. These actions were all inhibited by the superoxide scavenger Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC (100 μmol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering, characteristic nuclear morphology, in situ terminal deoxynucleotidyl trans...
