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 TGFßRI inhibitor, could facilitate cardiac repair in post-MI mice and induce the expansion of a Nkx2.5+ cardiomyoblast population. The present 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-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 down-regulation of Birc5 in post-injured mice hearts (n=6) to expand CPCs. Moreover, the increased Wnt3a in post-injured hearts could decrease CPCs, which could be reversed by A83-01 via inhibiting Fzd6 and WISP1 expressions in CPCs. Next, we used inducible aMHC-cre/mTmG mice to label cardiomyocytes with GFP and non-myocytes with RFP. We found A83-01 preserved more GFP+ myocytes (68.6±3.1% vs 80.9±3.0%; P<0.05, n=6) and fewer renewed RFP+ myocytes (0.026±0.005 vs 0.062±0.008%; P<0.05, n=6) in parallel with less cardiac fibrosis in isoprenaline-injected mice treated with A83-01. TGFßRI 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. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/stem.2216

View details for Web of Science ID 000370353200017

View details for PubMedID 26418219