Decorin-mediated transforming growth factor-beta 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-beta (TGF-beta) 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-beta pathway, was found to be inactivated after MCS (p < 0.02). Moreover, cultured human cardiac fibroblasts exposed to TGF-beta 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-beta pathway and its pro-fibrotic effects on the failing human heart.
Jahanyar
Jama
J
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. jahanyar@bcm.tmc.edu
Joyce
David L
DL
Southard
Robert E
RE
Loebe
Matthias
M
Noon
George P
GP
Koerner
Michael M
MM
Torre-Amione
Guillermo
G
Youker
Keith A
KA
D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D058575:Decorin; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006353:Heart-Assist Devices / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen