Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP

作者：Yuxi Sun, Mengqiu Ma, Dandan Cao, Ancheng Zheng, Yiying Zhang, Yang Su, Jianfang Wang, Yanhua Xu, Mi Zhou, Yansong Tang, Yifan Liu, Teng Ma, Aoyuan Fan, Xiaoying Zhang, Qiaoling Zhu, Jiachen Qin, Chunyang Mo, Yawei Xu, Li Zhang, Dachun Xu, Rui Yue · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.122.320781 · 被引用次数：84 · 研究领域：Cardiac Fibrosis and Remodeling、Peptidase Inhibition and Analysis、Signaling Pathways in Disease

Background: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) 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. Methods: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. 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 pos...