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. 2009 Dec 1;84(3):479-84.
doi: 10.1093/cvr/cvp249. Epub 2009 Jul 20.

C-reactive protein impairs the endothelial glycocalyx resulting in endothelial dysfunction

Sridevi Devaraj  1 , Jung-Mi Yun, Grete Adamson, Jose Galvez, Ishwarlal Jialal
Affiliations

C-reactive protein impairs the endothelial glycocalyx resulting in endothelial dysfunction

Sridevi Devaraj et al. Cardiovasc Res. .

Abstract

Aims: Inflammation is pivotal in atherosclerosis and a key early step is endothelial dysfunction. C-reactive protein, the prototypic marker of inflammation, and cardiovascular risk marker have been shown to promote atherogenesis. Increased levels of C-reactive protein are associated with endothelial dysfunction. The glycocalyx decorates the luminal surface and affords critical protection of the endothelium. Thus, the aim of the study was to examine the effect of C-reactive protein on the endothelial glycocalyx.

Methods and results: Human aortic endothelial cells (HAECs) were incubated with C-reactive protein at different concentrations (0, 12.5, 25, and 50 microg/mL) with boiled C-reactive protein as a control. For in vivo experiments, human C-reactive protein was injected into rats and human serum albumin was used as a control. Endothelial glycocalyx thickness was examined by transmission electron microscopy. Hyaluronan (HA) was examined in the supernatant of HAECs and in plasma and surface expression of heparan sulfate (HS) was quantified. C-reactive protein dose-dependently increased HA release in vitro and in vivo (P < 0.01). Also, glycocalyx thickness was significantly decreased (P < 0.05). Western blotting for HS showed significant reduction in expression of HS, one of the main glycosaminoglycans in the glycocalyx, with C-reactive protein treatment. There was a significant positive correlation between HA release and monocyte-endothelial cell adhesion, plasminogen activator inhibitor-1, and intercellular adhesion molecule-1 release and a negative correlation with endothelial nitric oxide synthase activity.

Conclusion: Collectively, these data suggest that C-reactive protein impairs glycocalyx function, resulting in endothelial dysfunction.

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Figures

Figure 1
Figure 1
Effect of C-reactive protein on HA release from HAECs. HAECs were treated with different concentrations of C-reactive protein (0, 12.5, 25, and 50 µg/mL) or boiled C-reactive protein (25 µg/mL) overnight at 37°C and HA release in the media was assessed by ELISA as described in Section 2. Data are mean ± S.D of eight experiments. *P < 0.01 compared with C.
Figure 2
Figure 2
Effect of C-reactive protein on HS levels in HAECs. HAECs were treated with different concentrations of C-reactive protein (0, 12.5, 25, and 50 µg/mL) or boiled C-reactive protein (25 µg/mL) overnight at 37°C and HS on cells was quantified by western blotting, using specific anti-human antibodies and using β-actin as a loading control as described in Section 2. Representative western blot and densitometric ratio for four different experiments are provided: 1, C; 2, C-reactive protein (12.5 µg/mL); 3, C-reactive protein (25 µg/mL); 4, C-reactive protein (50 µg/mL); 5, boiled C-reactive protein (25 µg/mL); *P < 0.05 compared with control and boiled C-reactive protein. Data are mean ± SD. *P < 0.05 compared with C.
Figure 3
Figure 3
Effect of C-reactive protein on glycocalyx thickness of HAECs. HAECs were treated with different concentrations of C-reactive protein (0, 25, and 50 µg/mL) or boiled C-reactive protein (25 µg/mL) overnight at 37°C and glycocalyx thickness was assessed by TEM as described in Section 2. (A) Mean ± SD of four experiments. *P < 0.01 compared with C. Representative micrographs are shown in (B).
Figure 4
Figure 4
Effect of C-reactive protein on glycocalyx in vivo. Wistar rats were treated with HuSA or human C-reactive protein (20 mg/kg body weight ip for 3 days) and aorta was removed for en face staining and for isolation of ECs as described in Section 2. Glycocalyx thickness was assessed by TEM as described in Section 2. Representative micrographs are shown in (A). Aorta was stained with antibodies to HS as described in Section 2 (B). (B,a) Negative control-no antibody, only PE; (B,b) HS staining with HuSA and (B,c) HS staining with human C-reactive protein.
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