Maggie M Hodges1, Carlos Zgheib2, Junwang Xu2, Junyi Hu2, Lindel C Dewberry2, Sarah A Hilton2, Myron W Allukian3, Joseph H Gorman4, Robert C Gorman4, Kenneth W Liechty2. 1. Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado. Electronic address: maggie.hodges@ucdenver.edu. 2. Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado. 3. Department of Pediatric Surgery, The University of Texas Health Science Center at Houston, Houston, Texas. 4. Department of Surgery and Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, Pennsylvania.
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)-β1 is a key regulator of ECM; therefore we hypothesize that TGF-β1 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-β1 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-β1 or a TGF-β1 receptor inhibitor (LY36497) to evaluate the effect of TGF-β1 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-β1 was not upregulated in fetal infarcts at any time point. Inhibition of the TGF-β1 receptor in adult cardiac fibroblasts decreased expression of col1a1, col3a1, MMP9, elastin, and TIMP1, whereas treatment of fetal cardiac fibroblasts with TGF-β1 increased expression of these genes. CONCLUSIONS: TGF-β1 is increased in adult infarcts compared with regenerative, fetal infarcts after MI. Although treatment of fetal cardiac fibroblasts with TGF-β1 conveys an adult phenotype, inhibition of TGF-β1 conveys a fetal phenotype to adult cardiac fibroblasts. Decreasing TGF-β1 after MI may facilitate myocardial regeneration by "fetalizing" the otherwise fibrotic, adult response to MI.
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)-β1 is a key regulator of ECM; therefore we hypothesize that TGF-β1 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-β1 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-β1 or a TGF-β1 receptor inhibitor (LY36497) to evaluate the effect of TGF-β1 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-β1 was not upregulated in fetal infarcts at any time point. Inhibition of the TGF-β1 receptor in adult cardiac fibroblasts decreased expression of col1a1, col3a1, MMP9, elastin, and TIMP1, whereas treatment of fetal cardiac fibroblasts with TGF-β1 increased expression of these genes. CONCLUSIONS: TGF-β1 is increased in adult infarcts compared with regenerative, fetal infarcts after MI. Although treatment of fetal cardiac fibroblasts with TGF-β1 conveys an adult phenotype, inhibition of TGF-β1 conveys a fetal phenotype to adult cardiac fibroblasts. Decreasing TGF-β1 after MI may facilitate myocardial regeneration by "fetalizing" the otherwise fibrotic, adult response to MI.