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Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection.

Abstract：

AIMS:The cardiac extracellular matrix is highly involved in regulating inflammation, remodelling, and function of the heart. Whether matrix alterations relate to the degree of inflammation, fibrosis, and overall rejection in the human transplanted heart remained, until now, unknown. METHODS AND RESULTS:Expression of matricellular proteins, proteoglycans, and metalloproteinases (MMPs) and their inhibitors (TIMPs) were investigated in serial endomyocardial biopsies (n = 102), in a cohort of 39 patients within the first year after cardiac transplantation. Out of 15 matrix-related proteins, intragraft transcript and protein levels of syndecan-1 and MMP-9 showed a strong association with the degree of cardiac allograft rejection (CAR), the expression of pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β, and with infiltrating CD3⁺ T-cells and CD68⁺ monocytes. In addition, SPARC, CTGF, TSP-2, MMP-14, TIMP-1, Testican-1, TSP-1, Syndecan-1, MMP-2, -9, and -14, as well as IL-6 and TGF-β transcript levels and inflammatory infiltrates all strongly relate to collagen expression in the transplanted heart. More importantly, receiver operating characteristic curve analysis demonstrated that syndecan-1 and MMP-9 transcript levels had the highest area under the curve (0.969 and 0.981, respectively), thereby identifying both as a potential decision-making tool to discriminate rejecting from non-rejecting hearts. CONCLUSION:Out of 15 matrix-related proteins, we identified synd-1 and MMP-9 intragraft transcript levels of as strong predictors of human CAR. In addition, a multitude of non-structural matrix-related proteins closely associate with collagen expression in the transplanted heart. Therefore, we are convinced that these findings deserve further investigation and are likely to be of clinical value to prevent human CAR.

journal_name

Eur Heart J

journal_title

European heart journal

authors

Vanhoutte D,van Almen GC,Van Aelst LN,Van Cleemput J,Droogné W,Jin Y,Van de Werf F,Carmeliet P,Vanhaecke J,Papageorgiou AP,Heymans S

doi

10.1093/eurheartj/ehs375

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

1930-41

issue

eissn

0195-668X

issn

1522-9645

pii

ehs375

journal_volume

pub_type

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Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection.