Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction. (October 2015)

• Record Type: Journal Article
• Authors: Tillmanns, Jochen; Hoffmann, Daniel; Habbaba, Yasmin; Schmitto, Jan D.; Sedding, Daniel; Fraccarollo, Daniela; Galuppo, Paolo; Bauersachs, Johann
• Is Part Of: Journal of molecular and cellular cardiology. Volume 87(2015:Oct.)
• Page Start: 194
• Page End: 203
• Publication Date: 2015-10
• Subjects: FAP fibroblast activation protein α -- APCE antiplasmin-cleaving enzyme -- rh recombinant human -- DPPIV dipeptidyl peptidase IV -- MI myocardial infarction -- LV left ventricular -- CF cardiac fibroblast; Fibroblast activation protein α -- Inflammation -- Myofibroblast -- Wound healing -- Heart -- Myocardial infarction; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.08.016
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Introduction: Fibroblast activation protein α (FAP) is a membrane-bound serine protease expressed by activated fibroblasts during wound healing in the skin. Expression of FAP after myocardial infarction (MI) and potential effects on cardiac wound healing are largely unknown. Methods: MI was induced in rats and FAP expression was analyzed at 3, 7 and 28 days post-MI by microarray, Western blot and immunohistochemistry. In human hearts after MI, a FAP + fibroblast population was identified, and characterized by immunohistochemistry for prolyl-4-hydroxylase β, α-smooth muscle actin, Thy-1 and vimentin. Signaling pathways leading to FAP expression were studied in human cardiac fibroblasts by Western blot and ELISA using TGFβ1, TGF-beta type I-receptor (TGFbR1)-inhibitor SB431542 or the MAPK-inhibitor U0126 as well as siRNA targeting SMAD2 and SMAD3. Finally, fibroblasts were assayed for FAP-dependent migration (modified Boyden-chamber), proliferation (BrdU-assay) and gelatinolytic activity by gelatin zymography. Results: In rats, FAP expression was increased after MI especially in the peri-infarct area peaking at 7 days post-MI. Co-localization analysis identified the majority of FAP + cells as activated proto-myofibroblasts and myofibroblasts. Concordantly, FAP + fibroblasts were abundant in ischemic tissue of human hearts after MI, but not in healthy control hearts. In vitro, FAP was induced by TGFβ1 via the canonical SMAD2/SMAD3 pathway. Depletion of FAP in fibroblasts reduced migratory capacity, while proliferation was not affected. Gelatin zymography revealed gelatinase activity by fibroblast-derived FAP. Conclusion: In this study, we show for the first time the expression of FAP in activated fibroblasts after MI and its activation by TGFβ1 . Effects of FAP on fibroblast migration and gelatinolytic activity indicate a potential role in cardiac wound healing and remodeling. Highlights: Fibroblast activation protein alpha (FAP) is expressed after MI in the heart. FAP expression identifies activated cardiac fibroblasts. FAP expression in cardiac fibroblasts is stimulated by TGFβ1 . FAP exerts gelatinolytic activity and mediates migration in cardiac fibroblasts.