Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration.

Abstract

AIMS:

Our previous study found that A83-01, a small molecule type 1 TGFβ 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 TGFβ 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.

• Authors: Wen-Pin Chen, Yuan-Hung Liu, Yi-Jin Ho, Sean M Wu
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 105 Issue 1 Pg. 44-54 (Jan 01 2015) ISSN: 1755-3245 [Electronic] England
• PMID: 25362681 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: [email protected].

Chemical References

• A-83-01
• Homeobox Protein Nkx-2.5
• Homeodomain Proteins
• Nkx2-5 protein, mouse
• Pyrazoles
• RNA, Small Interfering
• Receptors, Transforming Growth Factor beta
• Thiosemicarbazones
• Transcription Factors
• Green Fluorescent Proteins
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Animals
• Cell Differentiation
• Disease Models, Animal
• Female
• Gene Knockdown Techniques
• Green Fluorescent Proteins (genetics, metabolism)
• Homeobox Protein Nkx-2.5
• Homeodomain Proteins (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Transgenic
• Myoblasts, Cardiac (cytology, drug effects, physiology)
• Myocardial Infarction (drug therapy, pathology, physiopathology)
• Pregnancy
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• RNA, Small Interfering (genetics)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Regeneration (drug effects, physiology)
• Thiosemicarbazones (pharmacology)
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)