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Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.
Sun, Yuxi; Ma, Mengqiu; Cao, Dandan; Zheng, Ancheng; Zhang, Yiying; Su, Yang; Wang, Jianfang; Xu, Yanhua; Zhou, Mi; Tang, Yansong; Liu, Yifan; Ma, Teng; Fan, Aoyuan; Zhang, Xiaoying; Zhu, Qiaoling; Qin, Jiachen; Mo, Chunyang; Xu, Yawei; Zhang, Li; Xu, Dachun; Yue, Rui.
Afiliación
  • Sun Y; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Ma M; Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital (Y. Sun, A.Z., M.Z., L.Z.), Shanghai Jiao Tong University School of Medicine, China.
  • Cao D; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Zheng A; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Zhang Y; Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital (Y. Sun, A.Z., M.Z., L.Z.), Shanghai Jiao Tong University School of Medicine, China.
  • Su Y; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Wang J; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Xu Y; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Zhou M; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Tang Y; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Liu Y; Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital (Y. Sun, A.Z., M.Z., L.Z.), Shanghai Jiao Tong University School of Medicine, China.
  • Ma T; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Fan A; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Zhang X; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Zhu Q; Department of Cardiac Surgery, Ruijin Hospital (A.F.), Shanghai Jiao Tong University School of Medicine, China.
  • Qin J; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Mo C; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Xu Y; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Zhang L; Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, China (D.C., Y.Z., J.W., Yanhua Xu, X.Z., Q.Z., J.Q., C.M., R.Y.).
  • Xu D; Department of Cardiology, Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y. Sun, M.M., Y. Su, Yanhua Xu, Y.T., Y.L., T.M., Yawei Xu, D.X.).
  • Yue R; Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital (Y. Sun, A.Z., M.Z., L.Z.), Shanghai Jiao Tong University School of Medicine, China.
Circ Res ; 132(5): 586-600, 2023 03 03.
Article en En | MEDLINE | ID: mdl-36756875
ABSTRACT

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 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Péptido Natriurético Encefálico / Infarto del Miocardio Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Circ Res Año: 2023 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Péptido Natriurético Encefálico / Infarto del Miocardio Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Circ Res Año: 2023 Tipo del documento: Article