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

Abstract

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‐β‐gal‐positive senescent cardiac area (%SA‐β‐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‐β‐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 %EF 28 ± 9; female %EF 36 ± 7) was reversed in both PON+siRNA‐Notch1‐treated male (%EF 53 ± 9) and female mice (%EF 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.