Fig. 5: 4-oxo-RA preserves long-term cardiac function via Rarβ upon MI.

a, Experimental design to characterize HSC response after 4-oxo-RA in vivo treatment following MI. b, Alluvial plot of contribution from dTomato^pos and dTomato^neg cells to cardiac CD11b^pos myeloid cells in sham, vehicle and 4-oxo-RA upon MI based on flow cytometry. The y axis is reduced for visualization purposes. c, Flow-cytometry-based plots, illustrating the percentage of dTomato^pos cell frequencies for the vehicle and 4-oxo-RA condition in the myocardium upon MI. Cell frequencies are normalized to the vehicle condition. Data are presented as mean ± standard deviation. Ordinary two-way ANOVA. n = 6 vehicle; n = 8 4-oxo-RA. d, GO term enrichment of DEGs (top 200 log₂FC, adjusted P value <0.05) in MI + vehicle compared with MI + 4-oxo-RA dTomato^pos myeloid cells based on scRNA-seq. e, UMAP plot of 4-oxo-RA mouse cardiac CD11b^pos cells scRNA-seq upon MI, based on projection on previously shown vehicle scRNA-seq. The colours indicate the predicted cell type annotation. n = 2 vehicle; n = 3 4-oxo-RA. f, UMAP density plots of vehicle and projected 4-oxo-RA mouse cardiac CD11b^pos cells scRNA-seq upon MI depicting relative cell abundance. g, Bar plot of quantified relative cluster abundance in MI + vehicle and projected MI + 4-oxo-RA mouse cardiac CD11b^pos cells scRNA-seq. h, Expression profiles of cytokines in cardiac cells in vehicle and 4-oxo-RA conditions in the reparative phase at day 10 after MI. Normalized mean relative to Oaz1 expression and relative to sham surgery is shown. Values are relative to the average per gene. n ≥ 4 per gene. i, Masson’s Trichrome staining for collagen deposition in myocardial zones in MI + vehicle and MI + 4-oxo-RA. The lines highlight the separated areas in representative images. Two-tailed unpaired t-test. n = 6 per condition. RZ, remote zone; BZ, border zone; IZ, infarct zone. j, Cardiac functional assessment by echocardiography. Left: graphic representation of echocardiography during diastole. Ao, ascending aorta; LV, left ventricle; LA, left atrium. Right: quantification of echocardiographic parameters: EF, stroke volume and end-diastolic volume, comparing the quality control at day 1 with the chronic phase function at day 28 across treatment conditions after MI. Ordinary one-way ANOVA. n = 7 sham; n = 12 vehicle; n = 13 4-oxo-RA. In b–g, cells were isolated in the acute phase at day 3 after MI. Data are presented as mean ± standard deviation. n indicates the number of biological replicates per condition. For b, c, h and j, three or more independent experiments were performed.

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