Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue

Figures

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  Fig. 1. Gross effects of oxaliplatin on murine hearts. A. Oxaliplatin significantly slowed resting heart rates after 8 weeks of treatment. By week 8, oxaliplatin-treated mice had a significantly lower resting heart rate. * p < 0.05, Anova B: Heart weight/body weight (HW/BW, mg/g) index for mice treated with oxaliplatin. Correlation between the heart size and the Heart weight/body weight index. The Pearson correlation between the size and the HW/BW = 0.86. C: Example images of the enlarged heart measured at greatest width in the ventricles. D: Right atrial histology from a mouse treated with oxaliplatin for 8 weeks. Inset box is magnified in E. There is interstitial infiltration by neutrophils and mononuclear cells; F: Ventricular histology near the apex of the mouse heart. Insert box is magnified in G. Focal myocardial necrosis is evident. This is a small focus of coagulative necrosis, with loss of cross-striations and loss of nuclei; H: Ventricular histology from near the right atrial appendage. Inset box is magnified in I. Focal myocardial necrosis is evident in the right atrial appendage that also shows infiltration of a small number of associated neutrophils. N = 5 per group, all males

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  Fig. 2. Effect of oxaliplatin on the RNA transcription in the heart. A: Volcano plot representation: threshold (FC) -1.25 and 1.25, threshold FDR < 0.05. Total number of identified genes in the heart = 13,755, upregulated = 1,636, downregulated = 972 (~ 19% genes affected). B: Heatmap of these DEGs: control dextrose-treated mice – top 4 rows, oxaliplatin -treated (bottom 5 rows). C: Top 10 processes affected by oxaliplatin by GO pathway enrichment analysis of upregulated DEGs indicates mitotic cell cycle and cell division processes as top affected pathways. D: Top 10 processes of downregulated DEGs point to fatty acid metabolism as the top affected pathways. The “Signal” metric represents score that integrates enrichment significance and effect size. Higher values indicate greater statistical significance of enrichment. RNA-seq analysis was performed on n = 4 control and n = 5 oxaliplatin-treated mice, following exclusion of one control sample due to low RNA quality

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  Fig. 3. FA transport from capillary lumen to endothelium is upregulated by oxaliplatin. Abbreviations: Lipoprotein lipase, LPL (Lpl), glycosylphosphatidylinositol-anchored protein 1 GPIHBP1 (Gpihbp1). CD36 FA transporter (Cd36). FA binding proteins 4 and 5, FABP4,5 (Fabp4 and Fabp5), FA translocase transport protein FATP1 (Slc27a1), heart FA binding protein 3, H-Fabp (Fabp3). Based on RNA-seq analysis on n = 4 control and n = 5 oxaliplatin-treated mice

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  Fig. 4. Fatty acids ß-oxidation pathways in cardiomyocytes mitochondria are strongly downregulated by oxaliplatin. Abbreviations: ACAA2, Acetyl-CoA Acyltransferase 2 (Acaa2), ACAT1, acetyl-CoA acetyltransferase 1 (Acat1), ACSL1, acyl-CoA synthetase long chain family member 1 (Acsl1); CACT, Carnitine acylcarnitine translocase (Slc25a20); CPT1B, Carnitine O-palmitoyltransferase 1 (Cpt1b); CPT2, Carnitine O-palmitoyltransferase 2 (Cpt2); ECHS1, enoyl-CoA hydratase, short chain 1 (Echs1); HADH, hydroxyacyl-CoA dehydrogenase (Hadh); HADHA and HADHB, hydroxyacyl-CoA dehydrogenase alpha and beta subunits of the mitochondrial trifunction protein complex (Hadha and Hadhb); H-FABP, heart fatty acid binding protein (Fabp3); LCAD, long chain acyl-CoA dehydrogenases (Acadl); MCAD, medium chain acyl-CoA dehydrogenase (Acadm); MTP, mitochondrial trifunction protein complex; OGDH, oxoglutarate dehydrogenase (Ogdh); SCAD, small chain acyl-CoA dehydrogenase (Acads); VLCAD, very long chain acyl-CoA dehydrogenases (Acadvl); VDAC, voltage dependent ion channels (Vdac1, Vdac2, or Vdac3). The pathway is derived from KEGG pathway map00071. No upregulated genes were detected. Based on RNA-seq analysis on n = 4…

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  Fig. 5. Glycolysis in cardiomyocytes is upregulated in the oxaliplatin treated mice. Abbreviations: ALDOA, aldolase A (Aldoa); ALDOB, aldolase B (Aldob); ENO1/2/3, enolase 1, 2 and 3 (Eno1, Eno2 and Eno3); FBP2, fructose-bisphosphatase 2 (Fbp2), GAPDH, glyceraldehyde-3-phosphate dehydrogenase (Gapdh); GCK, glucokinase (Gck); GLUT1, glucose transporter 1 (Slc2a1); GLUT3, glucose transporter 3 (Slc2a3); GLUT4, Insulin-responsive glucose transporter 4 (Slc2a4); GPI1, glucose-6-phosphate Isomerase 1 (Gpi1); HK1, HK2, HK3 hexokinase 1, 2 ,3 (HK1, HK2, Hk3); LDHA, LDHB, lactose dehydrogenase A, B (Ldh1,Ldhb); MCT1,MCT3,MCT6 monocarboxylic acid transporters 1, 3, 6 (Slc16a1, Slc16a3, Slc16a6); PGAM1, phosphoglycerate mutase 1 (Pgam1); PGAM2, phosphoglycerate mutase 2 (Pgam2); PGK1, phosphoglycerate Kinase 1, (Pgk1); PFKL, phosphofructokinase-liver type (Pfkl); PKFM, phosphofructokinase-muscle type (Pfkm); and PKFP, phosphofructokinase-platelet type (Pfkp); PKM, pyruvate kinase-muscle type (Pkm); TPI1, topoisomerase 1 (Tpi1). The schematics is in part based on KEGG Pathways and ref [55]. Based on RNA-seq analysis on n = 4 control and n = 5 oxaliplatin-treated mice