Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP

Abstract

RATIONALE: Myocardial infarction (MI) elicits cardiac fibroblast activation and ECM (extracellular matrix) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)—a prolyl-specific serine protease—is an important marker of activated cardiac fibroblasts after MI. OBJECTIVE: 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. METHODS AND RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function 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 cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: 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.

Plasma fibroblast activation protein is decreased in acute heart failure despite cardiac tissue upregulation

“…Therefore, our findings show that during the acute phase of HF, plasma FAP levels are decreased. Our results are in line with those of Sun Y et al, who observed in acute myocardial infarction that tissue levels of FAP were overexpressed while plasma FAP levels were decreased [ 13 ]. However, there is no explanation for this paradoxical reduction in plasma FAP levels.…”

“…Recently, Sun Y et al, observed in ischemic HF that tissue levels of FAP were overexpressed while plasma FAP levels were decreased [ 13 ]. Despite having been studied, little is known about this paradoxical reduction in plasma FAP levels.…”

“…Despite having been studied, little is known about this paradoxical reduction in plasma FAP levels. Some authors suggest that this behavior of plasma FAP is reminiscent of negative acute phase proteins, which could reflect a systemic inflammatory response [ 13 , 14 ]. Inflammation is accepted as an important pathophysiological factor in both acute and chronic HF predicting poor prognosis independently of left ventricular ejection fraction, although it appears to contribute in different ways to each type of HF [ 15 ].…”

CAR‐T cell therapeutic avenue for fighting cardiac fibrosis: Roadblocks and perspectives

“…However, it is only expressed at low levels in most normal adult mice or human tissues. 76,79 Several research showed that FAP expression plays vital roles in immunosuppression, 80 pro-angiogenesis, 81 and intracellular signaling regulation. 82 FAP has also demonstrated dipeptidyl-and endo-peptidase activity.…”

Expression of fibroblast activation protein-α in human deep venous thrombus

“…Further, among non-oncological diseases, FAP expression has been reported in idiopathic pulmonary fibrosis, autoimmune diseases, liver cirrhosis, myocardial infarction, and atherosclerosis [6]. Sun et al [10] reported that in mice, the inhibition of FAP expression improves cardiac function following myocardial infarction and prevents the overactivation of fibroblasts, thereby limiting scar formation. Therefore, FAP is an important target in the pathophysiology, diagnosis, and treatment of cancers and fibrotic diseases.…”