(Circulation. 2001;103:525.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Association of Thrombospondin-1 and Cardiac Allograft Vasculopathy in Human Cardiac Allografts
From Cardiovascular Medicine (X.-M.Z., P.L.), Department of Pathology (Y.H., R.N.M.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; and Department of Medicine (G.G.M.), Vanderbilt Medical Center, Nashville, Tenn.
Correspondence to Peter Libby, MD, Vascular Medicine and Atherosclerosis Unit, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Background—Despite the expression of angiogenic growth factors in transplanted hearts, neovessel formation appears scant. We therefore hypothesized that cardiac allografts contain endogenous inhibitors of angiogenesis. In particular, we tested the involvement in cardiac allografts of thrombospondin-1 (TSP-1), a matrix glycoprotein that inhibits angiogenesis and facilitates smooth muscle cell (SMC) proliferation.
Methods and
Results—Levels of TSP-1 mRNA in endomyocardial
biopsy samples of human cardiac allografts substantially exceeded those
in normal hearts. The ratio of TSP to GAPDH mRNA determined with
quantitative RT-PCR was 6.54±1.6 in cardiac allografts versus
0.26±0.02 (P=0.001) in normal
hearts. Analysis in sequential biopsies revealed a strong association
between persistent elevation of TSP-1 in allografts and the development
of cardiac allograft vasculopathy (CAV). The CAV score was 2.4±0.8 in
patients with persistent TSP-1 elevation compared with 0.2±0.2 in
patients without elevation
(P=0.001). Immunohistochemistry
demonstrated intense expression of TSP-1 in cardiac allografts,
predominantly in cardiac myocytes and neointimal SMCs. In vitro
experiments demonstrated that T cells expressed TSP-1, acidic
fibroblast growth factor, and vascular endothelial cell growth factor
on allogeneic stimulation. Cytokines known to be elevated in cardiac
allografts (interleukin-1ß, interferon-
, and tumor necrosis
factor-
) induced TSP-1 in SMCs but inhibited TSP-1 in endothelial
cells.
Conclusions—Persistent elevation of TSP-1 in cardiac allografts correlates with the development of CAV. Allogeneic stimulation induces angiogenic growth factors and TSP-1 in T cells. Cytokines differentially regulate TSP-1 expression in SMCs versus endothelial cells. Increased levels of TSP-1 in human cardiac allografts may alter vascular responses to angiogenic growth factors by inhibiting angiogenesis and promoting SMC proliferation characteristic of CAV.
Key Words: glycoproteins • growth factors • transplantation • coronary disease • cytokines
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