title: Cardioprotective Actions of TGFβRI Inhibition Through Stimulating Autocrine/Paracrine of Survivin and Inhibiting Wnt in Cardiac Progenitors.
abstract: Heart failure due to myocardial infarction (MI) is a major cause of morbidity and mortality in the world. We found previously that A83-01, a TGFβRI inhibitor, could facilitate cardiac repair in post-MI mice and induce the expansion of a Nkx2.5 + cardiomyoblast population. This study aimed to investigate the key autocrine/paracrine factors regulated by A83-01 in the injured heart and the mechanism of cardioprotection by this molecule. Using a previously described transgenic Nkx2.5 enhancer-green fluorescent protein (GFP) reporter mice, we isolated cardiac progenitor cells (CPC) including Nkx2.5-GFP + (Nkx2.5+), sca1+, and Nkx2.5+/sca1 + cells. A83-01 was found to induce proliferation of these three subpopulations mainly through increasing Birc5 expression in the MEK/ERK-dependent pathway. Survivin, encoded by Birc5, could also directly proliferate Nkx2.5 + cells and enhance cultured cardiomyocytes viability. A83-01 could also reverse the downregulation of Birc5 in postinjured mice hearts (n = 6) to expand CPCs. Moreover, the increased Wnt3a in postinjured hearts could decrease CPCs, which could be reversed by A83-01 via inhibiting Fzd6 and Wnt1-induced signaling protein 1 expressions in CPCs. Next, we used inducible αMHC-cre/mTmG mice to label cardiomyocytes with GFP and nonmyocytes with RFP. We found A83-01 preserved more GFP + myocytes (68.6% ± 3.1% vs. 80.9% ± 3.0%; p < .05, n = 6) and fewer renewed RFP + myocytes (0.026% ± 0.005% vs. 0.062% ± 0.008%; p < .05, n = 6) in parallel with less cardiac fibrosis in isoprenaline-injected mice treated with A83-01. TGFβRI inhibition in an injured adult heart could both stimulate the autocrine/paracrine activity of survivin and inhibit Wnt in CPCs to mediate cardioprotection and improve cardiac function.
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei City, Taiwan.
authors.forename: Yu-Sian
authors.initials: YS
authors.lastname: Ho
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei City, Taiwan.
authors.forename: Wan-Hsuan
authors.initials: WH
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei City, Taiwan.|Division of Cardiology, Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan.
authors.forename: Fen-Chiung
authors.initials: FC
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan University, Taipei City, Taiwan.
authors.forename: Wei-Pang
authors.initials: WP
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei City, Taiwan.
authors.forename: Lung-Chun
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Cardiovascular Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
authors.affiliation: Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei City, Taiwan.
authors.forename: Yu-Ru
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei City, Taiwan.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Chen
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects* / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D013882:Thiosemicarbazones / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C507011:A-83-01; C117749:Birc5 protein, mouse; D002316:Cardiotonic Agents; D051034:Inhibitor of Apoptosis Proteins; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D000077022:Survivin; D013882:Thiosemicarbazones; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Birc5; MEK/ERK; Nkx2.5; Survivin; Wnt3a; sca1