Deletion of Cardiac PAD2 Causes Diastolic Dysfunction in the Female Heart

Heart failure is a leading cause of death and disability worldwide, with aging women more likely than aging men to develop diastolic dysfunction (heart failure with preserved ejection fraction, HFpEF), for which no therapies currently exist. Post-translational modifications of cardiac proteins, such as citrullination catalyzed by peptidyl arginine deiminase 2 (PAD2), regulate diastolic function. Recent work from our group demonstrates that PAD2 expression robustly declines with age in the female heart and global deletion of PAD2 causes diastolic dysfunction in middle-aged female mice. To further investigate the consequences of loss of PAD2 in the female heart, we generated a novel model of inducible cardiac specific PAD2 knockout (PAD2 cKO). We hypothesized that deletion of cardiac PAD2 in the female heart would lead to diastolic dysfunction. To quantify heart function, we utilized echocardiography to assess early to late left ventricular filling (E/A), isovolumic relaxation time (IVRT), and ejection fraction (EF). Consistent with our hypothesis, young female PAD2 cKO mice showed a reduction in E/A with prolonged IVRT and a preserved EF compared to wild-type (WT) mice. Together, we propose that loss of PAD2 is a novel mechanism of diastolic dysfunction in the female heart. Ongoing work aims to identify the effects of cardiac PAD2 deletion in middle-aged and aged female mice. Future studies will also investigate the mechanisms associated with the loss of PAD2 expression and seek to understand how PAD2 regulates relaxation in the heart. Understanding the mechanism of PAD2 regulation may prove beneficial in the identification of HFpEF therapies for aging women. Wyoming Research Scholar Program, IDeA Networks for Biomedical Research Excellence This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.