{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:38:51Z","timestamp":1791121131935,"version":"4.1.0"},"reference-count":72,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"published-print":{"date-parts":[[2010,4]]},"abstract":"<jats:p>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 \u03bcM 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 \u201cenergy-related\u201d 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 \u201cdanger signaling\u201d is a prime component of toxic DXR action and can drive cardiac cells into pathology.<\/jats:p>","DOI":"10.1152\/ajpregu.00360.2009","type":"journal-article","created":{"date-parts":[[2010,1,7]],"date-time":"2010-01-07T03:36:33Z","timestamp":1262835393000},"page":"R1075-R1088","source":"Crossref","is-referenced-by-count":38,"title":["Early effects of doxorubicin in perfused heart: transcriptional profiling reveals inhibition of cellular stress response genes"],"prefix":"10.1152","volume":"298","author":[{"given":"Malgorzata","family":"Tokarska-Schlattner","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U884, Laboratory of Fundamental and Applied Bioenergetics, Integrative and Systems Biology, Joseph Fourier University, Grenoble, 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