Decorin-mediated Transforming Growth Factor- Inhibition Ameliorates Adverse Cardiac Remodeling Jama Jahanyar, MD, PhD, a David L. Joyce, MD, a Robert E. Southard, MD, a Matthias Loebe, MD, PhD, a,b George P. Noon, MD, a,b Michael M. Koerner, MD, PhD, b,c Guillermo Torre-Amione, MD, PhD, b and Keith A. Youker, PhD a,b 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- (TGF-) 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- pathway, was found to be inactivated after MCS (p  0.02). Moreover, cultured human cardiac fibroblasts exposed to TGF- 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- pathway and its pro-fibrotic effects on the failing human heart. J Heart Lung Transplant 2007;26:34 – 40. Copyright © 2007 by the International Society for Heart and Lung Transplantation. Recent studies have implicated the disruption of extra- cellular matrix (ECM) homeostasis in effecting the progression to heart failure through increased ventric- ular fibrosis. 1–3 Several cytokines have been implicated in this process of cardiac remodeling, with transforming growth factor- (TGF-)–mediated SMAD2 activation serving as a potential mechanism for increased collagen deposition, which is the hallmark of myocardial fibro- sis. 4 Implantation of a left ventricular assist device (LVAD) has been shown to improve myocardial func- tion by promoting regression of fibrosis in the process of reverse remodeling. 1,3,5 The molecular mechanisms involved in reverse remodeling of the ECM after me- chanical circulatory support (MCS) have not been fully characterized. Recent attention has focused on changes in the quantity and composition of the ECM. 1,4 The ECM acts as a dynamic structural and functional support network within the myocardium, maintaining myocyte and myofibril integrity and alignment, as well as provid- ing force transduction and maintaining ventricular ge- ometry. Matrix metalloproteinases (MMPs) and tissue inhibi- tors of matrix metalloproteinases (TIMPs) have been implicated in alterations in the regulation of collagen degradation and tissue remodeling, and are thought to play a major role in both the progression to heart failure as well as recovery after MCS. 4,6 The increase in inter- stitial fibrosis follows an imbalance in both the synthesis of the ECM and its degradation by MMPs, and each may contribute to the matrix protein deposition seen in heart failure. 7 Decorin is a member of the small leucine-rich family of proteoglycans and has been found to affect the From the a Michael E. DeBakey Department of Surgery, Baylor College of Medicine; b Methodist DeBakey Heart Center, The Methodist Hos- pital; and c Department of Medicine, Baylor College of Medicine, Houston, Texas. Submitted July 26, 2006; revised September 29, 2006; accepted October 17, 2006. Reprint requests: Jama Jahanyar, MD, PhD, Michael E. DeBakey Department of Surgery, Division of Transplant and Assist Devices, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Telephone: 713-790-3155. Fax: 713-797-0613. E-mail: jahanyar@bcm.tmc.edu Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2006.10.005 34 FAILING HEART— BASIC SCIENCE