Association of Thrombospondin-1 and Cardiac Allograft Vasculopathy in Human Cardiac Allografts

Zhao, Xiaoming; Hu, Yenya; Miller, Geraldine G.; Mitchell, Richard N.; Libby, Peter

doi:10.1161/01.cir.103.4.525

Cited by 50 publications

(46 citation statements)

References 24 publications

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“…This pattern is also similar to those observed for fibroblast growth factor (FGF) 19 and thrombospondin-1 (TSP-1). 20 In these studies, longitudinal analysis of FGF demonstrated that heart transplant recipients with late, elevated levels of FGF had an increased severity of CAV, whereas recipients who had low levels of FGF generally had no or mild CAV. A comparable observation was found with TSP-1, in that patients who had an initial elevation of TSP-1 followed by baseline levels had less severe CAV.…”

Section: Discussionmentioning

confidence: 98%

Allograft Inflammatory Factor-1 Expression Correlates With Cardiac Rejection and Development of Cardiac Allograft Vasculopathy

et al. 2002

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Background— Standard morphological features of endomyocardial biopsy specimens do not necessarily correlate with the efficacy of immunotherapy or development of cardiac allograft vasculopathy (CAV). We hypothesized that expression of allograft inflammatory factor-1 (AIF-1), a cytokine-inducible, calcium-binding protein associated with vascular smooth muscle cell proliferation, would be associated with allograft rejection and development of CAV. Methods and Results— A total of 157 endomyocardial biopsy specimens from 26 patients with heart transplants were examined for expression of AIF-1 mRNA by semiquantitative reverse transcription–polymerase chain reaction. A significant relation was found between the International Society for Heart and Lung Transplantation rejection grade and expression of AIF-1 ( P <0.001). The calculated odds ratio indicates that a biopsy has 2.5 times the chance of AIF-1 expression per grade of rejection. The relative concentrations of AIF-1 and GAPDH mRNA were calculated and the resulting ratios indicated that the amount of AIF-1 mRNA expression is relative to the rejection grade ( P <0.02). In grade 1 biopsy specimens, AIF-1 was localized to infiltrating immune cells. In grade 3 biopsy specimens, AIF-1 was observed in immune cells and myocytes. AIF-1 is expressed in vascular and immune cells in coronary arteries with CAV, and persistent expression of AIF-1 in the allograft correlates with development of CAV ( P <0.002). Conclusions— Expression of AIF-1 in cardiac allografts correlates with rejection, and the amount of AIF-1 expressed correlates with the severity of rejection. AIF-1 is expressed in coronary arteries with CAV, and persistent expression of AIF-1 in the cardiac allograft is associated with development of CAV.

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Section: Discussionmentioning

confidence: 98%

Allograft Inflammatory Factor-1 Expression Correlates With Cardiac Rejection and Development of Cardiac Allograft Vasculopathy

et al. 2002

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“…NE results were normalized to the GAPDH result from the same reaction. 23 RNA from HL60 cells and fibroblasts served as a positive and negative control, respectively. …”

Section: Reverse Transcriptase-polymerase Chain Reactionmentioning

confidence: 99%

Neutrophil Elastase in Human Atherosclerotic Plaques

et al. 2003

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Background-Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease.Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheromarelated cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity. Methods and Results-Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (nϭ7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1␤, TNF-␣, or IFN-␥ but released it when stimulated by CD40 ligand, a cytokine found in atheroma. Conclusions-These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.

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“…Later studies showed that during the allogeneic response in vitro, T lymphocytes produce angiogenic growth factors including VEGF. 17,18 Thus, the observations of Nykänen et al 13 may have particular relevance to this special form of arteriosclerosis. In addition to angiopoietin, transplanted hearts can overexpress another endogenous modulator of angiogenesis.…”

Section: See P 1308mentioning

confidence: 96%

“…These data suggest that angiogenesis modulators, such as TSP-1, inhibit angiogenesis and promote smooth muscle cell proliferation, processes that promote transplantation arteriopathy. 18 What lessons can we draw from the tale of transplantation arteriopathy? First, the life-saving procedure of cardiac transplantation comes with a biological cost -a risk of obliterative arteriopathy -that too often replaces one disease with another.…”

Section: See P 1308mentioning

confidence: 99%