| First Author | Chen WP | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 105 |
| Issue | 1 | Pages | 44-54 |
| PubMed ID | 25362681 | Mgi Jnum | J:230304 |
| Mgi Id | MGI:5755940 | Doi | 10.1093/cvr/cvu229 |
| Citation | Chen WP, et al. (2015) Pharmacological inhibition of TGFbeta receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res 105(1):44-54 |
| abstractText | AIMS: Our previous study found that A83-01, a small molecule type 1 TGFbeta receptor inhibitor, could induce proliferation of postnatal Nkx2.5(+) cardiomyoblasts in vitro and enhance their cardiomyogenic differentiation. The present study addresses whether A83-01 treatment in vivo could increase cardiomyogenesis and improve cardiac function after myocardial infarction through an Nkx2.5(+) cardiomyoblast-dependent process. METHODS AND RESULTS: To determine the effect of A83-01 on the number of Nkx2.5(+) cardiomyoblasts in the heart after myocardial injury, we treated transgenic Nkx2.5 enhancer-GFP reporter mice for 7 days with either A83-01 or DMSO and measured the number of GFP(+) cardiomyoblasts in the heart at 1 week after injury by flow cytometry. To determine the degree of new cardiomyocyte formation after myocardial injury and the effect of A83-01 in this process, we employed inducible Nkx2.5 enhancer-Cre transgenic mice to lineage label postnatal Nkx2.5(+) cardiomyoblasts and their differentiated progenies after myocardial injury. We also examined the cardiac function of each animal by intracardiac haemodynamic measurements. We found that A83-01 treatment significantly increased the number of Nkx2.5(+) cardiomyoblasts at baseline and after myocardial injury, resulting in an increase in newly formed cardiomyocytes. Finally, we showed that A83-01 treatment significantly improved ventricular elastance and stroke work, leading to improved contractility after injury. CONCLUSION: Pharmacological inhibition of TGFbeta signalling improved cardiac function in injured mice and promoted the expansion and cardiomyogenic differentiation of Nkx2.5(+) cardiomyoblasts. Direct modulation of resident cardiomyoblasts in vivo may be a promising strategy to enhance therapeutic cardiac regeneration. |
