Sex-related differential susceptibility to ponatinib cardiotoxicity and differential modulation of the Notch1 signalling pathway in a murine model

Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukaemia, has proven cardiovascular toxicity. We assessed mechanisms of sex-related PON-induced cardiotoxicity and identified rescue strategies in a murine model. PON+scrambled siRNA-treated male mice had a higher number of TUNEL-positive cells (%TdT+6.12 +/- 0.17), higher percentage of SA-beta-gal-positive senescent cardiac area (%SA-beta-gal 1.41 +/- 0.59) and a lower reactivity degree (RD) for the survival marker Bmi1 [Abs (OD) 5000 +/- 703] compared to female (%TdT+3.75 +/- 0.35; %SA-beta-gal 0.77 +/- 0.02; Bmi1 [Abs (OD) 8567 +/- 2173]. Proteomics analysis of cardiac tissue showed downstream activation of cell death in PON+siRNA scrambled compared to vehicle or PON+siRNA-Notch1-treated male mice. Upstream analysis showed beta-oestradiol activation, and downstream analysis showed activation of cell survival and inhibition of cell death in PON+scrambled siRNA compared to vehicle or PON+siRNA-Notch1-treated female mice. PON+scrambled siRNA-treated mice also had a downregulation of cardiac actin-more marked in males-and vessel density-more marked in females. Female hearts showed greater cardiac fibrosis than their male counterparts at baseline, with no significant change after PON treatment. PON+siRNA-scrambled mice had less fibrosis than vehicle or PON+siRNA-Notch1-treated mice. The left ventricular systolic dysfunction showed by PON+scrambled siRNA-treated mice (male ï 28 +/- 9; female ï 36 +/- 7) was reversed in both PON+siRNA-Notch1-treated male (ï 53 +/- 9) and female mice (ï 52 +/- 8). We report sex-related differential susceptibility and Notch1 modulation in PON-induced cardiotoxicity. This can help to identify biomarkers and potential mechanisms underlying sex-related differences in PON-induced cardiotoxicity.