Reducing Heart Failure Prevalence and Increasing Survival after Myocardial Infarction by Targeting Peptidylarginine Deiminase 4

Background: Acute coronary syndromes continue to carry substantial morbidity and mortality despite advances in revascularization strategies. Sustained inflammation and fibrosis predict the development of heart failure (HF) following myocardial infarction (MI). The calcium-dependent enzyme peptidylarginine deiminase 4 (PAD4) catalyzes post-translational protein citrullination linked to HF pathogenesis, playing a crucial role in gene regulation during cardiac remodeling. This study aimed to assess PAD4’s role in cardiac regeneration following experimental MI.

Methods: Male WT, PAD4−/− mice, and WT mice treated with the pan-PAD inhibitor BB-Cl⁻Amidine underwent MI via permanent LAD ligation to investigate for potential clinical application. Padi4 expression and histone citrullination were analyzed in cardiac tissue from mice and post-mortem human samples. Cardiac troponin and apoptosis markers were quantified during the early post-MI phase (days 1–3), while cardiac leukocyte recruitment was assessed by flow cytometry. Bulk RNA-seq of cardiac tissue was performed on days 1 and 7 post-MI, followed by microarray analysis to investigate gene expression profiles of cardiac monocytes/macrophages (Mo/Mφ) and cardiac fibroblasts (CFs) on day 7. Fibrosis was quantified by MTC staining on days 7 and 28 post-MI, and cardiac function was assessed by echocardiography at all time points (days 1, 7, and 28).

Results: Cardiac Padi4 expression increased in mice and humans post-MI. On day 1 after surgery, Padi4 ablation reduced immune cell recruitment, cell necroptosis, and cardiac inflammation. On day 7, isolated PAD4−/− Mo/Mφ displayed a reparative phenotype with reduced inflammatory gene expression, while isolated PAD4−/− CFs showed diminished fibrotic pathways, leading to smaller infarct scars and less fibrosis. Consequently, PAD4−/− mice showed improved cardiac function. Early pharmacological PAD inhibition worsened cardiac outcomes including cardiac function, whereas later inhibition starting at day 7 post-MI reduced fibrosis and improved survival to a similar degree as found in PAD4−/− mice.

Conclusion: Padi4 ablation suppresses key processes in adverse remodeling and HF development, leading to significantly improved long-term survival. These findings underscore PAD4’s potential as a therapeutic target.

Publication History

Article published online:
11 February 2025