All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity
Fig 5
ATRA is cardioprotective in doxorubicin-treated mice as demonstrated by histological analysis.
(a) Representative image of cytoplasmic vacuolization in H&E-stained heart tissue section of doxorubicin-only treated mice. The arrow indicates cytoplasmic vacuolization. A zoomed-in view of the cytoplasmic vacuolization is shown on top. Scale bars, 100 μm. (b) Number of cardiomyocytes with vacuolated cytoplasm in the H&E-stained tissue sections of control (saline-treated), doxorubicin-only-treated, and ATRA + doxorubicin-treated mice (N = 5 mice per group). Data are presented as mean ± standard deviation. Statistical analysis was performed using a one-way ANOVA and Dunnett’s multiple comparisons correction (control vs. doxorubicin: *P = 0.0435, control vs. ATRA + doxorubicin: P = ns). (c) Representative image of TUNEL-stained heart tissue sections of doxorubicin-only treated, and ATRA + doxorubicin-treated mice. The arrow indicates TUNEL-positive cardiomyocyte. Scale bars, 100 μm. (d) TUNEL staining to detect DNA fragmentation during apoptosis. The graph depicts the number of TUNEL-positive cardiomyocytes/mm2 in the tissue sections of control (saline-treated), doxorubicin-only treated, and ATRA + doxorubicin-treated mice (N = 5 mice per group). Data are presented as mean ± standard deviation. Statistical analysis was performed using one-way ANOVA and Bonferroni multiple comparisons adjustment. Statistical comparisons between the saline-treated condition vs. doxorubicin-treated groups are shown above the bar, comparison between doxorubicin-only treated vs. ATRA + doxorubicin is shown with a bracket (*, **, and **** denote P = 0.0376, P = 0.0055 and P < 0.0001, respectively). (e) Representative images of Masson’s trichrome-stained tissue sections from control (saline-treated), doxorubicin-only treated, and ATRA + doxorubicin-treated mice. The arrow indicates focal fibrosis. Scale bars, 200 μm.