Mechanisms of cardiac protection by pirfenidone in the post-myocardial infarction setting

Abstract

Abstract Background A high proportion of patients with ST-segment elevation myocardial infarction (STEMI) experience adverse left ventricular (LV) remodelling despite guideline-recommended therapy. An excessive and dysregulated fibrotic response is involved in LV remodelling, and could be targeted by anti-fibrotic drugs such as pirfenidone, which is an approved treatment for idiopathic pulmonary fibrosis. Methods We evaluated the mechanisms of action of pirfenidone in the post-MI setting through sampling method-based mathematical models, enriched with transcriptomic data of swine experimental models of MI translated to the human proteome. Results The analysis of proteins modulated by pirfenidone shows that pirfenidone has a strong impact on several pathways involved in post-MI remodeling (Figure). The inhibition of p38γ-MAPK12 and furin displays the most prominent role on post-MI remodeling when compared to the other pirfenidone targets (PAI-1 and GLI2). p38γ-MAPK12 blockade inhibits cardiomyocyte apoptosis mediated by BCL2 and BAX. Myocardial hypertrophy and inflammation might be modulated by pirfenidone through the regulation of proteins downstream to p38γ-MAPK12, such as the NFATC1/NFATC2/NFATC3 pathway, and the transcription factors FOXO1, FOXO3 and NFκB, which are involved in TNFα regulation. The transcription factor AP-1 (homo-heterodimers of c-JUN/c-FOS), also downstream to p38γ-MAPK12, regulate the expression of genes involved in hypertrophy, fibrosis and inflammation (for example, IFNγ) By blocking both p38γ-MAPK12 and furin, pirfenidone can modulate extracellular matrix remodelling and cardiac fibrosis by targeting the TGFβ1-SMAD2/3 pathway, known to be highly involved in the progression of myocardial fibrosis, and other effector proteins such as MMP2 and MMP14 metalloproteases, PDGFA/B, and IGF1, many found to be involved also in myocardial fibrosis, impaired myocyte contractility and cell hypertrophic response. Conclusions We have identified several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodelling. These findings support future research regarding pirfenidone's clinical benefit in post-MI patients. Funding Acknowledgement Type of funding sources: None.