Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion

Tóth, Ambrus; Jeffers, John; Nickson, Philip; Jiang, Min; Morgan, James I.; Zambetti, Gerard P.; Erhardt, Péter

doi:10.1152/ajpheart.01046.2005

Cited by 122 publications

(106 citation statements)

References 58 publications

(87 reference statements)

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“…A potential role of the p53 target PUMA, commonly known to be upregulated after genotoxic stress in cancer cells [34], has also been suggested to be relevant for cardiomyocyte apoptosis in response to DOX as observed for H9C2 cardiomyoblasts [35]. 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.…”

Section: Pathways Of Cardiomyocyte Apoptosis Relevant To Dox -Inducedmentioning

confidence: 66%

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 -Inducedmentioning

confidence: 66%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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“…One of the best known and most important regulators of PUMA is p53, which is described as tumor suppressor protein [23][24][25][26][27][28]37]. Regulation of PUMA activity may also be determined by the activity of p73 [38,39], Sp1 [38], FoxO3a [40,41], E2F1 [39,42], CHOP [43][44][45][46][47][48], TRB3 [24], AP-1 [48] and c-Myc [49,50].…”

Section: Regulation Of Puma Activitymentioning

confidence: 99%

“…The pro-apoptotic activity of PUMA is also involved in the removal of damaged cells under conditions of ischemia/reperfusion. These conditions can lead to irreversible damage in cells and tissues, heart attack, and neurological diseases [43,46,47]. Alterations in PUMA p53-independent expression and apoptosis of damaged cells were described under such conditions.…”

Section: Puma In P53-independent Apoptosismentioning

confidence: 99%

“…It is not entirely clear how the activation of PUMA expression occurs during ischemia/reperfusion. The major transcription factors engaged in PUMA expression in these pathological conditions seem to be: E2F1, p73 and the ER stress-specific transcription factor C/EBP homologous protein (CHOP) [43,46,47]. As mentioned above, ER stress can also lead to apoptosis running with the involvement of PUMA [44,45,48,[62][63][64].…”

Section: Puma In P53-independent Apoptosismentioning

confidence: 99%

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Puma, a critical mediator of cell death — one decade on from its discovery

Hikisz

Kiliańska

2012

Cellular and Molecular Biology Letters

109

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Abbreviations used: ADI/II -activation domain I/II; Apaf-1 -apoptosis protease activating factor-1; Bad -Bcl-2 associated death promoter; Bak -Bcl-2 antagonist killer; Bax -Bcl-2 associated protein x; Bcl-2 -B-cell leukemia/lymphoma-2; BH1-4 -Bcl-2 homology domains 1-4; Bid -BH3 interacting domain death agonist; Bik -Bcl-2 interacting killer; Bim -Bcl-2 interacting mediator of cell death; Bmf -Bcl-2 modifying factor; Bod -Bcl-2-related ovarian death gene; Bok -Bcl-2 ovarian killer; BS1/2 -p53 binding site 1/2; CHOP -C/EBP homologous protein; DEN -diethylnitrosamine; GSK-3 -glycogen synthase kinase-3; HRK -harakiri, activator of apoptosis ; HSPCs -hematopoietic stem/progenitor cells; HSV-1 -human herpes virus; IKK -IκB kinase; IL-3 -interleukin 3; Lys -lysine; Mcl-1 -myeloid cell leukemia-1; MEFs -mouse embryo fibroblasts; miRNA/miR -microRNA; MLS -mitochondrial localization signal; MOMPmitochondrial outer membrane permeabilization; NOXA (PMAP1) -phorbol-12-myristate-13-acetate-induced protein 1; OMM -outer mitochondrial membrane; PCDprogrammed cell death; PI3K -phosphoinositide 3-kinase; PUMA -p53 upregulated modulator of apoptosis; ROS -reactive oxygen species; Ser -serine; Smac/DIABLOsecond mitochondria-derived activator or caspases/direct IAP binding protein with low pI; TRB3 -tribbles 3 homolog; UV-IR -ultraviolet-gamma irradiation Abstract: PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial Unauthenticated Download Date | 5/11/18 3:27 AM CELLULAR & MOLECULAR BIOLOGY LETTERS 647 membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

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“…For example Pumadeficient mice have been shown to be resistant to cardiomyocyte death following ischemia reperfusion. 35 Independently of p53, PUMA has been shown to promote apoptosis following stimulation with TNFα, and this is a result of increased expression of the Puma gene mediated by the p65 component of NFκB. 36 Apoptosis in vivo following sub-lethal whole-body ionizing radiation were almost exclusively p53-depdent in the bone marrow, spleen, thymus and GI tract (Fig.…”

Section: Methodsmentioning

confidence: 99%

The relative contribution of pro-apoptotic p53-target genes in the triggering of apoptosis following DNA damage in vitro and in vivo

Kuribayashi

Finnberg²,

Jeffers³

et al. 2011

Cell Cycle

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Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion

Cited by 122 publications

References 58 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Puma, a critical mediator of cell death — one decade on from its discovery

The relative contribution of pro-apoptotic p53-target genes in the triggering of apoptosis following DNA damage in vitro and in vivo

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