Limiting prolonged cardiac fibroblast (CF) activation and excessive extra cellular matrix (ECM) deposition is essential to preserve heart function after myocardial infarction. Recently, we reported that hyaluronan esters of butyric and retinoic acids (HBR) remarkably recovered myocardial performance after direct injection into infarcted rat hearts, substantially decreasing fibrous scarring. Here, we investigated whether the antifibrotic response was due to direct effect of HBR on CFs. Neonatal rat CFs were treated for 24–96h with increasing HBR concentrations (0.5–1.5g/l). HBR did not affect cell viability, neither induced apoptosis nor necrosis, but caused a proliferative arrest. HBR reduced both Collagen I mRNA and content, while increasing the gene expression and protein activity of metalloprotease 2 and 9, indicating a transcriptional intervention. Moreover, HBR downregulated a-sma mRNA and inhibited CF to myofibroblasts transition, accounting for the majority of ECM deposition. Therefore, HBR can significantly counteract myocardial fibrosis through the transcriptional regulation of CF genes.
Hyaluronan mixed esters of butyric and retinoic acid act transcriptionally on cardiac fibroblasts decreasing myocardial scarring in infarcted hearts
LIONETTI, Vincenzo;
2011-01-01
Abstract
Limiting prolonged cardiac fibroblast (CF) activation and excessive extra cellular matrix (ECM) deposition is essential to preserve heart function after myocardial infarction. Recently, we reported that hyaluronan esters of butyric and retinoic acids (HBR) remarkably recovered myocardial performance after direct injection into infarcted rat hearts, substantially decreasing fibrous scarring. Here, we investigated whether the antifibrotic response was due to direct effect of HBR on CFs. Neonatal rat CFs were treated for 24–96h with increasing HBR concentrations (0.5–1.5g/l). HBR did not affect cell viability, neither induced apoptosis nor necrosis, but caused a proliferative arrest. HBR reduced both Collagen I mRNA and content, while increasing the gene expression and protein activity of metalloprotease 2 and 9, indicating a transcriptional intervention. Moreover, HBR downregulated a-sma mRNA and inhibited CF to myofibroblasts transition, accounting for the majority of ECM deposition. Therefore, HBR can significantly counteract myocardial fibrosis through the transcriptional regulation of CF genes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
