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01.12.2012 | Original investigation | Ausgabe 1/2012 Open Access

Cardiovascular Diabetology 1/2012

ROCK inhibitor fasudil attenuated high glucose-induced MCP-1 and VCAM-1 expression and monocyte-endothelial cell adhesion

Zeitschrift:
Cardiovascular Diabetology > Ausgabe 1/2012
Autoren:
Hailing Li, Wenhui Peng, Weixia Jian, Yuanmin Li, Qi Li, Weiming Li, Yawei Xu
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2840-11-65) contains supplementary material, which is available to authorized users.

Competing interest

The authors had no conflicts of interest to declare in relation to this article.

Authors’ contributions

XYW and PWH designed, coordinated and wrote the manuscript. LHL coordinated and wrote the manuscript, performed cell culture, RT-PCR and western blot. JWX, LYM and LWM carried out the sample collection. JWX performed ELISA. LQ and LHL performed statistical analysis. All authors read and approved the final manuscript.

Abstract

Background

Previous studies suggested that the RhoA/ROCK pathway may contribute to vascular complications in diabetes. The present study was designed to investigate whether ROCK inhibitor fasudil could prevent high glucose-induced monocyte-endothelial cells adhesion, and whether this was related to fasudil effects on vascular endothelial cell expression of chemotactic factors, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1).

Methods

HUVECs were stimulated with high glucose (HG) or HG + fasudil in different concentration or different time. Monocyte-endothelial cell adhesion was determined using fluorescence-labeled monocytes. The mRNA and protein expression of VCAM-1 and MCP-1 were measured using real-time PCR and western blot. The protein levels of RhoA, ROCKI and p-MYPT were determined using western blot analysis. ELISA was employed to measure the expression of soluble VCAM-1 and MCP-1 in cell supernatants and human serum samples.

Results

Fasudil significantly suppressed HG-induced adhesion of THP-1 to HUVECs. Fasudil reduced Rho/ROCK activity (as indicated by lower p-MYPT/MYPT ratio), and prevented HG induced increases in VCAM-1 and MCP-1 mRNA and protein levels. Fasudil also decreased MCP-1 concentration in HUVEC supernatants, but increased sVCAM-1 shedding into the media. In human diabetic subjects, 2 weeks of fasudil treatment significantly decreased serum MCP-1 level from 27.9 ± 10.6 pg/ml to 13.8 ± 7.0 pg/ml (P < 0.05), while sVCAM-1 increased from 23.2 ± 7.5 ng/ml to 39.7 ± 5.6 ng/ml after fasudil treatment (P < 0.05).

Conclusions

Treatment with the Rho/ROCK pathway inhibitor fasudil attenuated HG-induced monocyte-endothelial cell adhesion, possibly by reducing endothelial expression of VCAM-1 and MCP-1. These results suggest inhibition of Rho/ROCK signaling may have therapeutic potential in preventing diabetes associated vascular inflammation and atherogenesis.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 7
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Literatur
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