Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice

Hochhauser, Edith; Kivity, Shaye; Offen, Daniel; Maulik, Nilanjana; Otani, Hajime; Barhum, Yael; Pannet, Hannah; Shneyvays, Vladymir; Shainberg, Asher; Goldshtaub, Valeri; Tobar, Anna; Vidne, Bernardo A.

doi:10.1152/ajpheart.00783.2002

Cited by 184 publications

(136 citation statements)

References 35 publications

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“…A similar PUMAdependency of cardiomyocyte apoptosis has been found in ischemia-reperfusion model of cultured cardiomyocyte [36]. This pathway would also involve BCL2-protein interaction [37,38], BAX/BAK-induced MOMP [39] and activation of initiator and activator caspases [24,39,40] similar to the above presented canonical intrinsic apoptosis in cancer cells. Likewise, invocation of the extrinsic apoptosis program by DOX via FAS-L or TRAIL ligands has also been detected in cardiomyocytes similar to cancer cells [41,42], potentially attaining robust caspase-3 activation by invoking MOMP (type II cells, Fig 1).…”

Section: Pathways Of Cardiomyocyte Apoptosis Relevant To Dox -Inducedsupporting

confidence: 67%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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Section: Pathways Of Cardiomyocyte Apoptosis Relevant To Dox -Inducedsupporting

confidence: 67%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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“…Cellular apoptosis plays an important role in maintaining homeostasis, cell differentiation, and development; in fighting against pathogens; and in the removal of inflammatory cells 21. However, in models of myocardial ischemia, cellular apoptosis was found to aggravate ischemic damage, while reducing apoptosis reduced ischemic injury 23. It seems likely that the increase of apoptosis exacerbated the ischemic damage within the deep dermal zone of burn wounds and thus participated in the burn wound progression.…”

Section: Discussionmentioning

confidence: 99%

Role of Autophagy and Apoptosis in Wound Tissue of Deep Second‐degree Burn in Rats

Xiao

et al. 2014

Acad Emerg Med

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ObjectivesThe pathogenesis of burn wound progression is poorly understood. Contributing factors include continuous loss of blood perfusion, excessive inflammation, and elevated apoptosis levels in wound tissue. Macroautophagy (here referred to simply as “autophagy”) is associated with many chronic diseases. The authors hypothesized that autophagy is involved in burn wound progression in a rat model of deep second‐degree burn.MethodsDeep second‐degree burns were modeled using a brass rod heated to 100°C applied for 6 seconds to the back skin of Wistar rats. Full‐thickness biopsies were obtained from burned and nonburned controls at several times postburn. Western blotting and immunohistochemical (IHC) staining determined expression of the autophagy markers Light Chain 3 (LC3) and beclin‐1. Apoptosis was determined by terminal‐deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay and laser Doppler flowmetry (LDF)‐measured tissue perfusion. Myeloperoxidase (MPO) activity assay measured inflammation. Hematoxylin and eosin (H&E) and Masson's trichrome staining–determined pathology and wound depth.ResultsThe LC3 and beclin‐1 protein level in burn wounds decreased to one‐fourth of normal levels (p < 0.01) over 24 hours and then began to increase but still did not reach their normal level. TUNEL‐positive cells in burn wounds were 3.7‐fold (p < 0.01) elevated over 48 hours and then decreased slightly, yet still remained higher than in normal skin. The burn wound progressed in depth over 72 hours. In addition, significant decrease in LDF values and upregulation of MPO activity were observed. Enhanced LC3‐positive cells were observed in the deep dermal layer of burn wounds as shown by IHC staining.ConclusionsA reduction in autophagy and blood flow and an increase in apoptosis and inflammation were observed in burn wounds early during the course of burn injury progression. This suggests that autophagy, complemented by apoptosis, play important roles in burn progression. Enhanced autophagy in the deep dermis may be a prosurvival mechanism against ischemia and inflammation after burn injury.

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“…In particular, activation of Bax has been reported in myocytes and hearts during I/R, and genetic deletion of Bax reduces infarct size. 28) These pro-death members of the Bcl-2 family permeabilize the outer membrane to an extent that allows the release of pro-apoptotic proteins from the inter-membrane space, most notably Smac/DIA-BLO. 9,12) In addition to upregulating/activating this pro-death protein family, there is a concomitant decrease in the antiapoptotic family members such as Bcl-2 during I/R injury.…”

Section: Discussionmentioning

confidence: 99%

B-Type Natriuretic Peptide-Induced Cardioprotection against Reperfusion Is Associated with Attenuation of Mitochondrial Permeability Transition

Sun

Zhang

Yan

et al. 2009

Biological & Pharmaceutical Bulletin

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Ischemia/reperfusion (I/R) injury occurs in a wide spectrum of disorders ranging from cardiac arrest to acute myocardial infarction and represents a major public health concern.1) Myocardial ischemia induces several pathological changes due to lack of oxygen supply, and post-ischemic reperfusion always worsens the injury. B-type natriuretic peptide (BNP) is a counter-regulatory peptide hormone predominantly synthesized in the ventricular myocardium. BNP is released into the circulation in response to excessive stretching of heart muscle cells, and reflects ventricular wall stress and tissue hypoxia.2) And BNP has been a widely used clinical biomarker for the diagnosis, prognosis, and treatment of heart failure.3,4) Our previous results, in this issue, demonstrated BNP enhanced hypoxia-induced apoptosis in cardiomyocytes.5) However, recent study showed that BNP attenuated reperfusion-induced heart dysfunction by reducing infarct size.6) These paradox effects of BNP seem like its clinical risk that an increased short-term risk of death with recombinant BNP use. 7) Thus the molecular and cellular mechanisms underlying the effect of BNP in myocardial injury have not been completely elucidated.Cardiac reperfusion is associated with dysfunctions in mitochondria that can progress to irreparable myocardial damage. In addition to cellular energy metabolism, mitochondria also have been recognized as key players in regulation of cell death in cardiac injury such as that occurs during I/R. The role of mitochondria during I/R is particularly critical because of the conditions that promote both apoptosis by the mitochondrial pathway and necrosis by irreversible damage to mitochondria in association with mitochondrial permeability transition (MPT). MPT is caused by the opening of mitochondrial permeability transition pores (mPTP) in the inner mitochondrial membrane, leading to matrix swelling, outer membrane rupture, release of apoptotic signaling molecules and irreversible injury to the mitochondria. 8) When I/R-induced cellular dysfunctions converge on mitochondria, especially when accompanied by high Ca 2ϩ concentrations and oxidative stress, mitochondria undergo massive swelling and become uncoupled as a result of the opening of mPTP. 9) If mPTP remains open, cells cannot maintain ATP levels. This will lead to the subsequent release of apoptotic proteins and induce cell death. 10) Another possible mechanism for mPTP opening is that pro-apoptotic Bcl-2 family and second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with a low isoelectric point (Smac/DIABLO) are believed to regulate the release through mPTP.11) Similarly these proteins play crucial roles in cardiomyocyte apoptosis induced by myocardial reperfusion injury. Growing evidence support the concept that pharmacological inhibition of the mPTP is an effective and promising strategy for the protection of the heart against reperfusion injury.12) Previous studies showed that BNP protected cardiomyocyte by opening of mit...

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Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice

Cited by 184 publications

References 35 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Role of Autophagy and Apoptosis in Wound Tissue of Deep Second‐degree Burn in Rats

B-Type Natriuretic Peptide-Induced Cardioprotection against Reperfusion Is Associated with Attenuation of Mitochondrial Permeability Transition

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