Key result
Cardiac PAD2 deletion induces diastolic dysfunction, hypertrophy, and fibrosis in female mice but not males.
Why the study?
Heart failure is sexually dimorphic, with women more likely to develop diastolic dysfunction, and global PAD2 knockout induces diastolic dysfunction in female mice. The cardiac-specific role of PAD2 remained unknown.
Does cardiac-specific deletion of PAD2 cause diastolic dysfunction in male and female mice?
Does cardiac-specific deletion of PAD2 cause diastolic dysfunction in male and female mice?
Cardiac-specific deletion of PAD2 induces diastolic dysfunction, hypertrophy, and fibrosis in female but not male mice, highlighting a sex-specific mechanism relevant to HFpEF pathogenesis.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for PAD2 modulation in female HFpEF; leaves open translation from animal models to human therapies.
Heart failure is sexually dimorphic, with women being more likely than men to develop diastolic dysfunction, a phenotype associated with heart failure with preserved ejection fraction (HFpEF). This subtype of heart failure currently has no approved therapies. Post-translational modifications (PTM) of myocardial proteins are important regulators of heart function. Citrullination is one such PTM that contributes to normal diastolic function. Its catalyzing enzyme, peptidyl arginine deiminase 2 (PAD2), has been shown to regulate this aspect of cardiac performance. Our group uncovered that PAD2 declines significantly with age, and global PAD2 knockout induces diastolic dysfunction in middle-aged female mice. Because these findings point to a key role in maintaining normal myocardial relaxation, we sought to further investigate the cardiac-specific role of PAD2. We generated a novel inducible, cardiac-specific PAD2 knockout (PAD2 cKO). We hypothesized that deletion of cardiac PAD2 in female mice would lead to diastolic dysfunction. Echocardiography and invasive pressure-volume loop analysis was used to evaluate cardiac structure and function in male and female PAD2 cKO mice. Young female PAD2 cKO mice exhibited a diastolic dysfunction phenotype across both assessments, including prolonged isovolumic relaxation (elevated IVRT and Tau), impaired passive left ventricular filling (reduced E/A ratio), preserved ejection fraction, and increased end-diastolic pressure, indicating abnormal relaxation and increased chamber stiffness. Male PAD2 cKO mice did not display this phenotype of impaired diastolic function, instead they maintain normal heart function. Morphological analyses revealed hypertrophy and fibrosis in the female PAD2 cKO mice compared to wild-type controls. Ongoing work aims to identify mechanisms by which loss of PAD2 causes diastolic dysfunction. Together, these findings may ultimately aid in the continued development of therapeutic strategies for HFpEF in the aging female heart. This abstract was presented at the American Physiology Summit 2026 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.
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Schmitt et al. (2026) studied Diastolic dysfunction. Cardiac-specific PAD2 knockout vs. Wild-type controls was evaluated on Cardiac structure and function evaluated by echocardiography and invasive pressure-volume loop analysis. Cardiac-specific deletion of PAD2 in young female mice induced diastolic dysfunction, hypertrophy, and fibrosis, whereas male PAD2 knockout mice maintained normal heart function.
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