Pharmacological Inhibition of Peptidylarginine Deiminases (PADs) Aggravates Cardiac Damage and Increases the Mortality Rate Following Myocardial Infarction in Mice

All articles of this category (opens in new window) Background: While advancements in prompt revascularization strategies mitigate ischemic damage, subsequent molecular cascades perpetuate adverse postmyocardial infarction (post-MI) remodeling, characterized by sustained inflammation and excessive fibrosis. Consequently, a substantial proportion of MI survivors progress to heart failure (HF). Peptidylarginine deiminases (PADs), which catalyze protein citrullination, have been implicated in the regulation of inflammatory and profibrotic pathways. Here, we studied the effects of the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A) on cardiac function following MI in mice. Methods: MI was induced in male wild-type (WT) mice via permanent ligation of the left anterior descending (LAD) artery. One group received daily treatment with BB-Cl-amidine (1 mg/kg body weight). On day 1 post-MI, plasma levels of cardiac troponin T (cTnT), cell-free DNA (cfDNA), and interleukin-6 (IL-6) were quantified, while infarct size was assessed through TTC staining. Bulk RNA sequencing on infarcted hearts was conducted to assess global changes in gene expression. Cardiac function was evaluated via transthoracic echocardiography, with body weight and survival rates monitored through day 7 post-MI. Results: BB-Cl-amidine treatment strongly diminished cardiac PAD activities, as evidenced by reduced citrullination of histone H3. Elevated levels of cTnT, cfDNA, IL-6, and increased infarct size on day 1 post-MI indicated exacerbated myocardial injury induced by BB-Cl-amidine. RNA sequencing revealed pronounced downregulation of potassium channel genes by the inhibitor, suggesting increased susceptibility to life-threatening arrhythmogenesis post-MI. Echocardiography disclosed a marked deterioration in left ventricular (LV) systolic function, accompanied by ventricular dilatation and wall thinning on day 1 post-MI. LV diameter in inhibitor-treated mice reached a maximum on day 7. Consequently, mice treated with BB-Cl-amidine showed an alarming 80% mortality by day 7 post-MI, along with significant body weight loss compared to WT mice, indicating systemic deterioration. Conclusion: PAD inhibition in acute MI exacerbates myocardial injury, impairs LV function, and reduces survival in mice. These findings highlight the need for therapeutic strategies that account for timing to effectively target PADs and prevent adverse remodeling without impairing early repair. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany