Abstract 19905: C-Reactive Protein Plays a Causal Role in Adverse Remodeling in Vein Bypass Grafts
Introduction: C-reactive protein (CRP) antigen and mRNA are present in the vascular wall of obstructed human vein grafts (VGs) at concentrations significantly greater than those present in normal veins. However, it is unknown whether CRP actively regulates VG intimal hyperplasia or is simply a biomarker associated with VG disease. We employed a murine model of VG disease and transgenic mice that express human CRP under control of the native CRP promoter to test the hypothesis that CRP promotes adverse remodeling in VGs.
Methods and Results: Segments of inferior vena cava from wild-type (WT) and CRP-transgenic (CRP-Tg) donor mice were grafted into carotid arteries of recipient WT or CRP-Tg mice. Four weeks later intimal hyperplasia in VG was measured. Intimal hyperplasia was significantly greater (P<0.05) in VG of CRP-Tggraft/CRP-Tgrecipient mice (182±49.2×103 μm2, n=5) than in VG of WTgraft/CRP-Tgrecipient mice (107±19.2×103 μm2, n=5) or WTgraft/WTrecipient mice (109±18.8×103 μm2, n=7). Plasma CRP levels were 24.6, 17.5, and 0 μg/mL in these 3 groups, respectively. Together, these results suggested that localized expression of CRP in VG stimulates intimal hyperplasia. Purified CRP (16–32 μg/mL) increased in vitro migration rates of cultured venous murine smooth muscle cells (SMC) 4.2–6.7-fold, respectively, compared to control SMC lacking CRP (P<0.05), but had no significant effect on SMC proliferation. Macrophage migration into VG neointima, assessed by quantitative immunohistochemistry, was significantly greater (P<0.05) in both CRP-Tggraft/CRP-Tgrecipient mice and WTgraft/CRP-Tgrecipient mice than in WTgraft/WTrecipient mice. Expression of plasminogen activator inhibitor-1 (PAI-1) in VG endothelial cells, assessed by immunohistochemistry, was also significantly greater (P<0.05) in both CRP-Tg recipient groups than in WTgraft/WTrecipient mice, though plasma PAI-1 levels did not differ between groups.
Conclusions: A primary increase in CRP expression significantly increases intimal hyperplasia, SMC migration, macrophage infiltration, and PAI-1 expression in VG. These results suggest a causal role of CRP in adverse VG remodeling under clinically relevant conditions.
- © 2010 by American Heart Association, Inc.