Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling

Dhingra, Rimpy; Margulets, Victoria; Chowdhury, Subir Roy; Thliveris, James A.; Jassal, Davinder S.; Fernyhough, Paul; Dorn, Gerald W.; Kirshenbaum, Lorrie A.

doi:10.1073/pnas.1414665111

Cited by 185 publications

(148 citation statements)

References 42 publications

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“…CYP27B1 , which was 13.23-fold up-regulated in CEM/ADR5000 cells, is important for drug metabolism74. BNIP3 plays role in oxidative stress75 and was 10.41-fold up-regulated in our resistant cell line. TCF7 is an anti-apoptotic gene76 and was 17.66-fold down-regulated.…”

Section: Discussionmentioning

confidence: 81%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

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We systematically characterised multifactorial multidrug resistance (MDR) in CEM/ADR5000 cells, a doxorubicin-resistant sub-line derived from drug-sensitive, parental CCRF-CEM cells developed in vitro. RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed. Chromosomal aberrations were identified by array-comparative genomic hybridisation (aCGH) and multicolour fluorescence in situ hybridisation (mFISH). Fifteen ATP-binding cassette transporters and numerous new genes were overexpressed in CEM/ADR5000 cells. The basic karyotype in CCRF-CEM cells consisted of 47, XX, der(5)t(5;14) (q35.33;q32.3), del(9) (p14.1), +20. CEM/ADR5000 cells acquired additional aberrations, including X-chromosome loss, 4q and 14q deletion, chromosome 7 inversion, balanced and unbalanced two and three way translocations: t(3;10), der(3)t(3;13), der(5)t(18;5;14), t(10;16), der(18)t(7;18), der(18)t(21;18;5), der(21;21;18;5) and der(22)t(9;22). CCRF-CEM consisted of two and CEM/ADR5000 of five major sub-clones, indicating genetic tumor heterogeneity. Loss of 3q27.1 in CEM/ADR5000 caused down-regulation of ABCC5 and ABCF3 expression, Xq28 loss down-regulated ABCD1 expression. ABCB1, the most well-known MDR gene, was 448-fold up-regulated due to 7q21.12 amplification. In addition to well-known drug resistance genes, numerous novel genes and genomic aberrations were identified. Transcriptomics and genetics in CEM/AD5000 cells unravelled a range of MDR mechanisms, which is much more complex than estimated thus far. This may have important implications for future treatment strategies.

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Section: Discussionmentioning

confidence: 81%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

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“…BNIP3 is an important regulator of cardiomyocyte mitochondrial function and survival during ischemic/hypoxia injury [10, 47]. That is, the mitochondrial perturbations triggered by BNIP3 gene activation were found to parallel opening of the mitochondrial permeability transition pore, mitochondrial membrane potential loss, and cell death [48]. Although HIF-1α is an upstream molecular target of BNIP3, [22] we showed that HIF-1α did not completely parallel the alterations in BNIP3, suggesting that there may be other unrecognized upstream molecular pathways involved in BNIP3 regulation in RV failure.…”

Section: Discussionmentioning

confidence: 99%

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

et al. 2017

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BackgroundRight ventricular structure and function is a major predictor of outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain poorly understood. Growing evidence suggests the importance of autophagy in cardiac remodeling; however, its dynamics in the process of right ventricle(RV) remodeling in PH has not been fully explored. We sought to study the time course of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are underlying mechanisms.MethodsRats were studied at 2, 4, and 6 weeks after subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed in rats. Autophagy structures and markers were assessed using transmission electron microscope, RT-qPCR, immunohistochemistry staining, and western blot analyses. Western blot was also used to quantify the expression of mTOR and Beclin-1 mediated pro-autophagy signalings in the RV.ResultsTwo weeks after MCT injection, pulmonary artery systolic pressure increased and mild RV hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks with moderately decreased function, whereas typical characteristics of RV decompensation and failure occurred at 6 weeks thus demonstrating the progression of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. Autophagy activation was coincident with increased pulmonary artery systolic pressure. Pro-autophagy signaling pathways were activated in a RV remodeling stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated protein kinase)-α were primarily upregulated and phospho-mTOR suppressed in the RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 3) and beclin-1 expression were relatively low during these stages, they were significantly upregulated after 6 weeks in this model.ConclusionsOur findings provide evidence of sustained activation of autophagy in RV remodeling of MCT induced PH model, while pro-autophagic signaling pathways varied depending on the phase.

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“…107 Bnip3 also stimulates myocardial necrosis in response to doxorubicin treatment by disrupting formation of mitochondrial protein complexes between the key respiratory proteins. 108 Thus, what determines the role of Bnip3 in promoting cell death or survival through mitochondrial autophagy remains to be elucidated in the heart.…”

Section: Nix/bnip3l and Bnip3mentioning

confidence: 99%

Molecular Mechanisms of Mitochondrial Autophagy/Mitophagy in the Heart

Saito

Sadoshima

2015

Circulation Research

271

211

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Mitochondrial quality is a crucial determinant of cell viability, and mitochondrial autophagy plays a central role in this control mechanism. Based on studies in yeast, numerous investigations of this process have been conducted and the framework of mammalian mitochondrial autophagy is progressively appearing. However, many enigmas about the molecular mechanisms involved remain unsolved. Furthermore, the pathological significance of mitochondrial autophagy in the heart remains largely unclear. In this review, we discuss the current understanding of mitochondrial autophagy in mammals with reference to that in yeast. Regarding the process in yeast, some points of uncertainty have arisen. We also summarize recent advances in the research of autophagy and mitochondrial autophagy in the heart. This article is a part of a review series on Autophagy in Health and Disease.

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Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling

Cited by 185 publications

References 42 publications

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

Molecular Mechanisms of Mitochondrial Autophagy/Mitophagy in the Heart

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