Early effects of doxorubicin in perfused heart: transcriptional profiling reveals inhibition of cellular stress response genes
| Autor: | Rita Guzun, Michael Zaugg, Malgorzata Tokarska-Schlattner, Eliana Lucchinetti, Séverine Gratia, Uwe Schlattner, Laurence Kay, Valdur Saks |
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| Přispěvatelé: | Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular Anesthesia Research Laboratory, University hospital of Zurich [Zurich], Institute of Cell Biology, Hamant, Sarah |
| Rok vydání: | 2010 |
| Předmět: |
Male
Phosphocreatine Transcription Genetic Physiology Pharmacology Polymerase Chain Reaction MESH: Down-Regulation MESH: Nucleic Acid Hybridization 0302 clinical medicine Adenosine Triphosphate Cellular stress response Gene expression MESH: Adenosine Triphosphate MESH: Up-Regulation MESH: Animals MESH: Oxygen Consumption media_common Oligonucleotide Array Sequence Analysis 0303 health sciences Nucleic Acid Hybridization Heart 3. Good health Mitochondria Up-Regulation 030220 oncology & carcinogenesis Toxicity MESH: Glycolysis DNA microarray Glycolysis medicine.drug Drug medicine.medical_specialty MESH: Rats MESH: Mitochondria media_common.quotation_subject Citric Acid Cycle Down-Regulation Biology MESH: Phosphocreatine MESH: Mitogen-Activated Protein Kinase Kinases 03 medical and health sciences MESH: Citric Acid Cycle MESH: Doxorubicin MESH: Gene Expression Profiling Oxygen Consumption MESH: RNA Physiology (medical) Internal medicine medicine [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Animals Doxorubicin [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology RNA Messenger Rats Wistar Gene 030304 developmental biology MESH: RNA Messenger Mitogen-Activated Protein Kinase Kinases Cardiotoxicity MESH: Transcription Genetic Gene Expression Profiling MESH: Polymerase Chain Reaction MESH: Rats Wistar MESH: Male Rats MESH: Heart Endocrinology MESH: Oligonucleotide Array Sequence Analysis RNA |
| Zdroj: | AJP-Regulatory, Integrative and Comparative Physiology AJP-Regulatory, Integrative and Comparative Physiology, American Physiological Society, 2010, 298 (4), pp.R1075-88. ⟨10.1152/ajpregu.00360.2009⟩ |
| ISSN: | 1522-1490 0363-6119 |
| DOI: | 10.1152/ajpregu.00360.2009⟩ |
| Popis: | International audience; Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its clinical application is limited by the risk of severe cardiac-specific toxicity, for which an efficient treatment is missing. Underlying molecular mechanisms are not sufficiently understood so far, but nonbiased, systemic approaches can yield new clues to develop targeted therapies. Here, we applied a genome-wide transcriptome analysis to determine the early cardiac response to DXR in a model characterized earlier, that is, rat heart perfusion with 2 muM DXR, leading to only mild cardiac dysfunction. Single-gene and gene set enrichment analysis of DNA microarrays yielded robust data on cardiac transcriptional reprogramming, including novel DXR-responsive pathways. Main characteristics of transcriptional reprogramming were 1) selective upregulation of individual genes or gene sets together with widespread downregulation of gene expression; 2) repression of numerous transcripts involved in cardiac stress response and stress signaling; 3) modulation of genes with cardiac remodeling capacity; 4) upregulation of "energy-related" pathways; and 5) similarities to the transcriptional response of cancer cells. Some early responses like the induction of glycolytic and Krebs cycle genes may have compensatory function. Only minor changes in the cardiac energy status or the respiratory activity of permeabilized cardiac fibers have been observed. Other responses potentially contribute to acute and also chronic toxicity, in particular, those in stress-responsive and cardiac remodeling transcripts. We propose that a blunted response to stress and reduced "danger signaling" is a prime component of toxic DXR action and can drive cardiac cells into pathology. |
| Databáze: | OpenAIRE |
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