The Role And Mechanisms Of Fibroblast Activation Protein After Myocardial Infarction

Myocardial infarction(MI)elicits cardiac fibroblast(CF)activation and extracellular matrix(ECM)deposition to maintain structural integrity of the heart.Recent studies demonstrate that fibroblast activation protein(Fap),a prolyl-specific serine protease,is an important marker of activated CFs after MI.This study aims to test whether Fap is a critical regulator of cardiac repair after MI,and to uncover the underlying cellular and molecular mechanisms for better treatment of MI.We found that FAP is up-regulated in patient CFs after cardiac injuries,while plasma FAP is down-regulated and functions as a prognostic marker for cardiac repair.Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac functions after MI.Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone,which promotes ECM deposition and alignment by CFs and prevents their overactivation,thereby limiting scar expansion.Mechanistically,we found that brain natriuretic peptide(BNP)is a novel substrate of Fap that mediates post-ischemic angiogenesis.Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation.Pharmacological inhibition of Fap in Nppb(encoding pre-pro BNP)or Npr1(encoding BNP receptor)deficient mice showed no cardioprotective effects,suggesting that BNP is a physiological substrate of Fap.Finally,we compared the therapeutic effect of FAPi with LCZ696,an enzyme inhibitor involved in the degradation of the BNP,and found similar cardioprotective effect between two drugs.Taken together,this study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI.Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.