TY - JOUR T1 - Eastern Regional Meeting 2021 JF - Journal of Investigative Medicine JO - J Investig Med SP - 901 LP - 941 DO - 10.1136/jim-2021-ERM VL - 69 IS - 4 A2 - , Y1 - 2021/04/01 UR - http://hw-f5-jim.highwire.org/content/69/4/901.abstract N2 - Sharon George1Anna Gams1Alexi Kiss3Gregory Trachiotis2Tatiana Efimova3Igor R Efimov11Biomedical Engineering, The George Washington University, Washington, DC, USA2Washington DC VA Medical Center, Washington, DC, USA3The George Washington University, Washington, DC, USAPurpose of studyDoxorubicin (DOX), an anthracycline used in anti-cancer therapy, has significant cardiotoxic effects that cause cardiomyopathies. Activation of stress signaling molecules, including p38 MAPK isoforms p38α, p38β, p38γ and p38δ, has been implicated in the development of cardiotoxic effects. We previously demonstrated that p38δ deletion provides cardioprotection during DOX treatment in female but not in male mice. We hypothesized that DOX cardiotoxicity can similarly be attenuated by p38 inhibition in an isoform- and sex-specific manner in human organotypic cardiac slices.Methods usedSlices (400μm) were prepared from the left ventricle of human donor hearts that were not used in transplantation. Slices were cultured for 24 hours in the presence of DOX (0, 0.5, 1, 5, 10 and 50 μM) and 1) SB203580 (p38a/b inhibitor, 10μM), 2) Compound62 (pan p38 inhibitor, 1μM) or 3) p38 isoform-specific siRNA. Slices were optically mapped and conduction velocity (CV) was determined. Slices were fixed and RNAseq was performed.Summary of ResultsCV was reduced with increasing DOX dose, with 62% male slices and 29% female slices viable at the highest DOX dose of 50 μM. However, at 5 μM DOX, CV was reduced by 22% in males (21.7 to 16.7 cm/s) and 5% in females (21.0 to 20.0 cm/s). RNAseq revealed 1652 differentially expressed genes (DEGs) in male versus female DOX-treated slices while only 71 DEGs were observed between male versus female control slices. SB203580 failed to prevent DOX-induced CV slowing in mice of both sexes (19% and 18% CV reduction in males and females, respectively). On … ER -