Mechanisms of cardiac protection by pirfenidone in the post-myocardial infarction setting. (14th October 2021)

• Record Type: Journal Article
• Authors: Aimo, A; Iborra Egea, O; Bayes-Genis, A; Galvez-Monton, C; Burchielli, S; Passino, C; Emdin, M
• Is Part Of: European heart journal. Volume 42(2021)Supplement 1
• Publication Date: 2021-10-14
• Subjects: Pathophysiology and Mechanisms; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehab724.1066
• Languages: English
• ISSNs: 0195-668X

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. FUNDunding Acknowledgement: Type of funding sources: None.