doi: 10.1161/hh1201.093159
© 2001 American Heart Association, Inc.
Editorial |
Calcineurin, Mitochondrial Membrane Potential, and Cardiomyocyte Apoptosis
From the Department of Pediatrics, University of Cincinnati, Children’s Hospital Medical Center, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio.
Correspondence to Jeffery D. Molkentin, PhD, Children’s Hospital Medical Center, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}chmcc.org
Key Words: apoptosis • heart • calcineurin • mitochondria • ischemia
Mitochondria
comprise 
30% of the total intracellular volume within a mammalian
cardiomyocyte.1 2
Not surprisingly, subtle alterations in mitochondrial function or
membrane potential can have a dramatic influence on
cardiomyocyte energy production and, ultimately,
the health of an individual cell. Indeed, cellular injury or stress
stimulation directly elicits alterations in mitochondrial architecture,
membrane potential, and oxidative capacity, which are associated with
an irreversible loss of mitochondrial matrix contents and integral
membrane protein constituents such as cytochrome
c
oxidase.3 The release of
cytochrome c and/or
mitochondrial permeability transition directly mediates cellular
apoptosis through calcium-sensitive proteases or through
coupling proteins that coordinate the activation of caspases and DNA
fragmentation enzymes.3 Given
the high intracellular content of mitochondria in
cardiomyocytes and the unabated requirement for high-energy
phosphate carriers to maintain ionic gradients and active force
generation, coordinated disturbances in mitochondrial function
can dramatically affect cell survival.
Recent investigation has suggested an emerging paradigm
whereby stress-responsive intracellular signaling pathways directly and
indirectly influence mitochondrial membrane potential, oxidative
capacity, and the coupling of apoptosis initiating factors. For
example, stress-responsive signaling through the c-Jun N-terminal
kinases (JNKs) has been shown to initiate apoptosis in certain
cell types by directly influencing proteins within the mitochondrial
membranes.4 In addition,
increased expression of the mitochondrial stabilizing Bcl proteins can
be transcriptionally regulated through stress-responsive signaling
pathways, which subsequently antagonize mitochondrial dysfunction and
cytochrome c
release.5 Activation of the
intracellular kinase Akt also directly antagonizes
mitochondrial-directed apoptosis by phosphorylating the
mitochondrial destabilizing protein Bad, reducing cytochrome
c release and caspase
activation.6 Lastly,
activation of nuclear factor-
B (NF-B) signaling induces
expression of stress-adaptive proteins such as Bcl-2, antioxidants, and
calcium-regulating proteins.7
In general, signaling pathways such as the stress- and
mitogen-activated protein kinases (SAPKs and MAPKs), protein
kinase C (PKC), Akt, NF-B, and the calcium-activated
phosphatase calcineurin respond to extracellular stress and/or
receptor-activated signal transduction as a means of modulating
cell survival against diverse cytopathic stimuli. Given the critical
role of mitochondria in cellular homeostasis, additional pathways will
likely be elucidated whereby stress-responsive signaling pathways
adjust mitochondrial characteristics in an attempt to preserve
function, or alternatively, to coordinate cellular
apoptosis.
Adult cardiomyocytes are thought to be largely refractory to cell cycle reentry and cytokinesis.8 9 Thus, apoptotic events in the myocardium likely result in a cumulative decrease in cell number, which is thought to be a contributing factor in heart failure.10 The description of apoptosis in the failing myocardium was initially controversial, in part, due to unusually high approximations of overall levels. However, more recent calculations in several animal models of cardiomyopathy, as well as failed human hearts, have confirmed the increased occurrence of cardiomyocyte apoptosis as a potential contributing factor in the progressive loss of pump function.10 In contrast to the low but cumulative levels of apoptosis identified in the failing heart, acute myocardial infarction promotes massive apoptosis of cardiomyocytes due to a primary lack of oxygen and/or a reperfusion-induced hyperemia that is associated with free radical production.11 In response to ischemic injury or various forms of cardiomyopathy, many of the stress-responsive signaling pathways discussed above are activated or pathologically regulated.12 Indeed, stress-responsive signaling pathways not only coordinate alterations in cellular physiology and gene expression, but they also contribute to the regulation of cellular apoptosis.
One potential regulator of stress responses and apoptosis in cardiomyocytes is the calcium/calmodulin–activated protein phosphatase calcineurin (or PP2B). Calcineurin was initially identified as an important regulator of cardiomyocyte hypertrophy in vivo and in vitro.13 14 However, more recent investigation has suggested a role for calcineurin in the regulation of cardiomyocyte apoptosis. Such a concept is not unique to cardiomyocytes, as dozens of studies have previously identified a critical role for calcineurin as an effector of apoptosis in other cell types. Studies conducted in neurons, lymphocytes, and cancer cell lines have demonstrated either pro- or antiapoptotic effects of calcineurin activation.15 16 17 18 19 20 21 22 The exact decision of cytoprotection versus apoptosis is likely regulated by coordinated signals from other costimulated signaling pathways. Indeed, calcineurin activation was recently shown either to induce apoptosis or to antagonize apoptosis depending on the status of p38 MAPK activation.23 However, the role that calcineurin plays in regulating cardiomyocyte apoptosis and the potential modulatory effects of parallel regulatory pathways has not, until recently, been investigated.
In this issue of Circulation Research, Kakita et al24 identify an antiapoptotic effect associated with calcineurin activation in cardiomyocytes. Endothelin-1 stimulation of cardiomyocytes was protective against H2O2-induced TUNEL reactivity, DNA laddering, caspase-3 cleavage, and loss of mitochondrial membrane potential.24 Endothelin-1 stimulation also promoted NFAT dephosphorylation, which is a highly specific indicator of calcineurin activation. More importantly, endothelin-1–mediated cytoprotection from H2O2-induced apoptosis was blocked by inhibition of calcineurin with either cyclosporin A or FK506. These results suggest that calcineurin activation normally antagonizes cardiomyocyte apoptosis in response to H2O2 injury. The results of Kakita et al24 are supported and refuted by two recent studies discussed below.
De Windt et al14
reported that calcineurin activation protected
cardiomyocytes from apoptotic stimulation both in
vitro and in vivo, supporting the findings of Kakita et
al.24 Cultured neonatal
cardiomyocytes infected with an adenovirus encoding an
activated form of calcineurin were protected against
2-deoxyglucose–induced
apoptosis.14 More
importantly, transgenic mice expressing an activated form of
calcineurin in the heart were largely protected from
ischemia/reperfusion-induced DNA laddering, suggesting that
calcineurin activation antagonizes cardiomyocyte
apoptosis in vivo.14
In this same report, cyclosporin A also reversed the protective effects
of 
-adrenergic stimulation in the presence of 2-deoxyglucose
treatment in vitro. Collectively, De Windt et
al14 and Kakita et
al24 provide reasonable
support for the hypothesis that calcineurin activation is normally
cytoprotective in cardiomyocytes.
Molecular mechanisms associated with calcineurin-mediated cardioprotection have also been suggested. Kakita et al24 reported that calcineurin activation promoted an increase in Bcl-2 expression, suggesting a potential mechanism for downregulated apoptosis through enhanced mitochondrial membrane stability. Similarly, De Windt et al14 reported that calcineurin activation was associated with Akt phosphorylation, which also enhances mitochondrial membrane stability through Bad phosphorylation. However, it is uncertain if calcineurin directly regulates the expression of antiapoptotic cellular machinery, or if calcineurin activation simply antagonizes apoptosis as a secondary consequence of initiating the entire hypertrophic program.
In contrast, Saito et al25 reported that isoproterenol stimulation of cardiac ß-adrenergic receptors promoted myocyte apoptosis, in part, by stimulating calcineurin activity. Saito et al25 demonstrated that cyclosporin A and FK506 blocked the increase in cardiomyocyte apoptosis induced by isoproterenol stimulation and, more significantly, that transgenic mice expressing dominant-negative calcineurin in the heart were refractory to isoproterenol-induced TUNEL reactivity in vivo. These results suggest that calcineurin activation is associated with enhanced apoptosis in cardiomyocytes. However, Saito et al25 also reported that transgenic mice expressing dominant-negative calcineurin in the heart have increased apoptosis in response to ischemia/reperfusion injury, supporting the contrary hypothesis that calcineurin activation is cardioprotective. These seemingly contradictory data underscore the complexity of intracellular signaling networks within mammalian cells, such that related stress stimuli can elicit fundamentally different responses. Indeed, the most probable explanation for such divergent data, which are even manifested within a single report, is that calcineurin signaling is interpreted within a molecular context of other signaling pathways. This interpretation is also supported by the observed dichotomous role of calcineurin in regulating apoptosis of neurons and lymphocytes discussed above.15 16 17 18 19 20 21 22 23 Given these considerations, calcineurin is likely a more peripheral effector of apoptosis that depends on cellular context and coordinated actions of other signaling pathways.
The assertion that calcineurin can have both anti- and proapoptotic regulatory roles should be considered within context of the multiple mechanisms whereby a cell can undergo apoptosis (mitochondrial- versus death receptor–mediated). In addition, the interpretation of the role of calcineurin as an apoptotic regulator can be complicated by known side effects of the often-used calcineurin inhibitor cyclosporin A. Most notably, cyclosporin A inhibits mitochondrial destabilization by directly binding to cyclophilin D, which associates with the adenine nucleotide translocator in the inner mitochondrial membrane to regulate permeability pore transition.26 Indeed, it is not valid to assume that the effects of cyclosporin A on apoptosis are mediated entirely by calcineurin inhibition. For example, cyclosporin A infusion can protect hearts from ischemia/reperfusion-induced injury by preventing mitochondrial permeability transition.27
That maintaining mitochondrial stability is critical for protecting cardiomyocytes from apoptotic stimuli, such as ischemia/reperfusion, is also highlighted by another report in this issue of Circulation Research. Akao et al28 demonstrate that maintenance of mitochondrial membrane potential through controlled activation of ATP-sensitive potassium channels prevents oxidative stress–induced cellular apoptosis in cultured cardiomyocytes. Indeed, emerging evidence suggests a paradigm whereby activation of ATP-sensitive potassium channels in the mitochondrial inner membrane can preserve membrane potential and is a significant mechanism of preconditioning-associated cytoprotection.29 30 Akao et al28 demonstrated that H2O2-induced loss of mitochondrial membrane potential and ensuing apoptosis were antagonized with the ATP-sensitive potassium channel–gating agent diazoxide. Diazoxide-mediated preservation of mitochondrial membrane potential was recently associated with a reversal in mitochondrial matrix contraction and a maintenance in mitochondrial intermembrane volumes, suggesting a structural mechanism underlying the observed protection.31 Collectively, these results underscore the importance of preserving mitochondrial function and architecture during noxious stimuli as a means of inhibiting cardiomyocyte apoptosis.
In summary, the literature supports a convergence of dissimilar mechanisms to collectively target the mitochondria in an attempt to fine-tune cellular viability in response to pleiotropic insults or agonist stimulation. Indeed, direct effectors of mitochondrial integrity, such as diazoxide and cyclosporin A, can function as potent suppressors of membrane destabilization and the subsequent initiation of apoptosis (although by different mechanisms). Furthermore, an emerging body of literature suggests that intracellular signaling pathways directly and indirectly regulate mitochondrial membrane stability and the apoptotic fate of a cell. Given the central position that mitochondria occupy in cardiomyocytes, future investigations into the mechanisms whereby signaling pathways affect mitochondrial stability will be particularly relevant. Indeed, a better understanding of the molecular effectors that modulate mitochondrial integrity will likely suggest new strategies for protecting cardiomyocytes from ischemic insults.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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