Decorin-mediated Transforming Growth Factor-β Inhibition Ameliorates Adverse Cardiac Remodeling

Background: Implantation of a left ventricular assist device (LVAD) has been shown to induce regression of fibrosis in patients with congestive heart failure (CHF) and improve myocardial function. The mechanism of reverse remodeling after mechanical circulatory support (MCS), however, has not been fully characterized. In this study we examined the anti-fibrotic effects of decorin, an extracellular matrix (ECM) proteoglycan, on the transforming growth factor-β (TGF-β) pathway. Methods: Human myocardial tissue samples were obtained from patients undergoing LVAD implantation and again following subsequent transplantation after a sustained period of MCS. The specimens were examined by utilizing different molecular and histologic techniques, including human cardiac fibroblast in vitro studies. We assessed gene expression, mRNA and protein levels. Results: We found a significant decrease in interstitial fibrosis after MCS, with a decrease in collagen mRNA transcription rates, serving as an indirect measurement of collagen synthesis. Both the mRNA and protein levels of decorin were significantly increased after a period of MCS. Decorin mRNA was up-regulated by 44% after MCS (p < 0.01), which paralleled the increase in interstitial decorin deposition (p < 0.001). In addition, p-SMAD2, a molecular marker downstream of the TGF-β pathway, was found to be inactivated after MCS (p < 0.02). Moreover, cultured human cardiac fibroblasts exposed to TGF-β demonstrated decreased collagen production when exogenous decorin was added (p < 0.03). Conclusions: The decorin molecule is potentially involved in reverse cardiac remodeling, by directly inhibiting the TGF-β pathway and its pro-fibrotic effects on the failing human heart.