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.

• Authors: Davy Vanhoutte, Geert C van Almen, Lucas N L Van Aelst, Johan Van Cleemput, Walter Droogné, Yu Jin, Frans Van de Werf, Peter Carmeliet, Johan Vanhaecke, Anna-Pia Papageorgiou, Stephane Heymans
• Journal: European heart journal (Eur Heart J) Vol. 34 Issue 25 Pg. 1930-41 (Jul 2013) ISSN: 1522-9645 [Electronic] England
• PMID: 23139380 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Cytokines
• Proteoglycans
• Tissue Inhibitor of Metalloproteinases
• Matrix Metalloproteinases

Topics

• Allografts
• Biomarkers (metabolism)
• Cytokines (metabolism)
• Extracellular Matrix (metabolism)
• Female
• Fibrosis (metabolism, pathology)
• Graft Rejection (metabolism, pathology)
• Heart Transplantation
• Humans
• Male
• Matrix Metalloproteinases (metabolism)
• Middle Aged
• Monocytes (pathology)
• Myocarditis (metabolism, pathology)
• Myocardium (pathology)
• Proteoglycans (metabolism)
• T-Lymphocytes (pathology)
• Tissue Inhibitor of Metalloproteinases (metabolism)