Differential Expression of Transforming Growth Factor-ß1 Is Associated With Fetal Regeneration After Myocardial Infarction.

ABSTRACT

BACKGROUND: Global extracellular matrix (ECM)-related gene expression is decreased after myocardial infarction (MI) in fetal sheep when compared with adult sheep. Transforming growth factor (TGF)-ß1 is a key regulator of ECM; therefore we hypothesize that TGF-ß1 is differentially expressed in adult and fetal infarcts after MI. METHODS: Adult and fetal sheep underwent MI via ligation of the left anterior descending coronary artery. Expression of TGF-ß1 and ECM-related genes was evaluated by ovine-specific microarray and quantitative polymerase chain reaction. Fibroblasts from the left ventricle of adult and fetal hearts were treated with TGF-ß1 or a TGF-ß1 receptor inhibitor (LY36497) to evaluate the effect of TGF-ß1 on ECM-related genes. RESULTS: Col1a1, col3a1, and MMP9 expression were increased in adult infarcts 3 and 30 days after MI but were upregulated in fetal infarcts only 3 days after MI. Three days after MI elastin expression was increased in adult infarcts. Despite upregulation in adult infarcts both 3 and 30 days after MI, TGF-ß1 was not upregulated in fetal infarcts at any time point. Inhibition of the TGF-ß1 receptor in adult cardiac fibroblasts decreased expression of col1a1, col3a1, MMP9, elastin, and TIMP1, whereas treatment of fetal cardiac fibroblasts with TGF-ß1 increased expression of these genes. CONCLUSIONS: TGF-ß1 is increased in adult infarcts compared with regenerative, fetal infarcts after MI. Although treatment of fetal cardiac fibroblasts with TGF-ß1 conveys an adult phenotype, inhibition of TGF-ß1 conveys a fetal phenotype to adult cardiac fibroblasts. Decreasing TGF-ß1 after MI may facilitate myocardial regeneration by "fetalizing" the otherwise fibrotic, adult response to MI.