Background: Investigating the effect of sex on pressure unloading therapy in a clinical scenario is limited by several non-standardized factors. Hence, we sought to study sex-related similarities and differences under laboratory conditions. Methods: Pressure overload was induced in male and female rats by aortic banding (AB) for 6 and 12 weeks. Age-matched sham operated animals served as controls. Pressure unloading was performed by aortic debanding at week 6. Different aspects of myocardial remodeling were characterized by echocardiography, pressure-volume analysis, histology, qRT-PCR and explorative proteomics. Results: Hypertrophy, increased fetal gene expression, interstitial fibrosis, and prolonged active relaxation were noted in the AB groups at week 6 in both sexes. However, decompensation of systolic function and further deterioration of diastolic function only occurred in male AB rats at week 12. AB induced similar proteomic alterations in both sexes at week 6, while characteristic differences were found at week 12. After debanding, regression of hypertrophy and recovery of diastolic function took place to a similar extent in both sexes. Nevertheless, fibrosis, transcription of β-to-α myosin-heavy chain ratio, and myocardial proteomic alterations were reduced to a greater degree in females compared to males. Debanding exposed anti-remodeling properties in both sexes, and prevented the functional decline in males. Conclusions: Female sex is associated with greater reversibility of fibrosis, fetal gene expression, and proteomic alterations. Nevertheless, pressure unloading exposes a more pronounced anti-remodeling effect on the functional level in males, which is attributed to the more progressive functional deterioration in AB animals.

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