Streptozotocin-induced hyperglycemia unmasks cardiotoxicity induced by doxorubicin

Figures

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  Fig. 1. Streptozotocin-induced hyperglycemia aggravates cardiac dysfunction and mortality induced by doxorubicin. (A) Schematic representation of the protocol used in vivo. (B) Kaplan-Meyer plot of mice surviving during the in vivo experimental protocol in the 4 groups of mice treated with saline (Ctl), doxorubicin (Dox), streptozotocin (STZ) or both (Dox-STZ). (C) Cardiac function evaluated by fractional shortening measured by transthoracic echocardiography (TTE) of mice after doxorubicin treatment (represented arrow Dox on the x-axis) and type 1 diabetes (represented by Stz on the x-axis). (D) Cleaved caspase 3 protein expression in the cardiac tissue evaluated by western blot. (E, F) mRNA expression of Bax and Bcl2, respectively measured in the cardiac tissue par RT-qPCR. *p < 0.05, **p < 0.01 and ***p < 0.001.

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  Fig. 2. Effect of doxorubicin and glucose on cardiomyocytes survival and size. (A) H9C2 Cardiomyocytes mortality 24h after doxorubicin (Dox), Glucose (Glc) or both (DoxGlc) treatment. (B, C) cross section of cultured H9C2 labeled with phalloidin (green). Ctl represent the non-treated condition. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to the “Ctl” condition. #p < 0.05 compared to the “Dox” condition.

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  Fig. 3. Effect of streptozotocin-induced hyperglycemia and doxorubicin on cardiomyocytes atrophy and capillary rarefaction. (A) Double immunostaining of vinculin (green) and caveolin-1 (red) proteins on cardiac sections of saline (Ctl), doxorubicin (Dox), streptozotocin (STZ) and both doxorubicin and diabetes (Dox-STZ) treated mice. Histograms indicate the cross-sectional area of myocytes (B) and the capillary/cardiomyocyte ratio (D) measured in the 4 groups. (C,E) protein expression of MuRF-1 and VEGF-A, respectively, measured in the cardiac tissue par western blot. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to the “Ctl” condition or otherwise specified. Scale, 100 µm.

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  Fig. 4. Streptozotocin-induced hyperglycemia aggravates cardiac fibrosis in doxorubicin treated mice. (A) Distribution of fibrillar collagens in the left ventricle of a mouse examined by polarized light microscopy after Sirius Red staining. (B) Semi-quantitative analysis of cardiac fibrosis. (C,D) protein expression of Galectin 3 and CD68, respectively, in the cardiac tissue. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to the “Ctl” condition. Scale, 100 µm.

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  Fig. 5. Scheme illustrating how type 1 diabetes aggravates the doxorubicin-induced cardiac dysfunction leading to mortality.