| First Author | Ho YS | Year | 2016 |
| Journal | Stem Cells | Volume | 34 |
| Issue | 2 | Pages | 445-55 |
| PubMed ID | 26418219 | Mgi Jnum | J:233089 |
| Mgi Id | MGI:5780769 | Doi | 10.1002/stem.2216 |
| Citation | Ho YS, et al. (2016) Cardioprotective Actions of TGFbetaRI Inhibition Through Stimulating Autocrine/Paracrine of Survivin and Inhibiting Wnt in Cardiac Progenitors. Stem Cells 34(2):445-55 |
| abstractText | 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 TGFbetaRI 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 alphaMHC-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. TGFbetaRI 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. |
