Reactive fibrosis precedes doxorubicin-induced heart failure through sterile inflammation.

摘要: Aims Doxorubicin (DOX)-induced heart failure has a poor prognosis, and effective treatments have not been established. Because DOX shows cumulative cardiotoxicity, we hypothesized that minimal cardiac remodelling occurred at the initial stage in activating fibroblasts. Our aim was to investigate pathophysiology of DOX-exposed fibroblasts propose prophylaxis. Methods results An animal study performed using lower dose (4 mg/kg/week for 3 weeks, i.p.) than toxic dose. Histological analysis with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay, picrosirius red staining, immunohistochemical staining. The mechanism analysed vitro low DOX, which did induce cell apoptosis. Microarray performed. Differentially expressed genes were confirmed by enrichment analysis. Mitochondrial damage assessed mitochondrial membrane potential. production inflammatory cytokines fibrosis markers western blot, quantitative polymerase chain reaction, ELISA. A phosphokinase antibody array detect related signalling pathways. Low-dose induced death, localized perivascular area mice. suggested associated innate immune system reactions, resulting remodelling. increased expression interleukin-1. also promoted fibrotic markers, such as alpha smooth muscle actin galectin-3. These responses through stress-activated protein kinase/c-Jun NH2-terminal kinase signalling. peroxisome proliferator-activated receptor (PPARγ) agonist attenuated suppressing kinase. Furthermore, this molecule suppressed DOX-induced early vivo. Conclusions provoked reactive sterile inflammation evoked damaged mitochondria.