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Statins attenuate high mobility group box-1 protein induced vascular endothelial activation : a key role for TLR4/NF-κB signaling pathway

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Abstract

High mobility group box-1 (HMGB1) has recently been implicated as a proinflammatory cytokine that plays critical roles in endothelial dysfunction and atherosclerosis. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, exerts anti-inflammatory effects in the cardiovascular system beyond its cholesterol-lowering property. The aim of our study was to investigate whether atorvastatin inhibits HMGB1-induced vascular endothelial activation, and elucidate the underlying molecular mechanism. In this study, we found that atorvastatin, at concentrations ranging from 0.1 to 10 μM, effectively and in a dose-dependent manner inhibited HMGB1-induced endothelial cells (ECs) activation. Incubation of ECs with 10 μM atorvastatin reduced adhesion molecules (ICAM-1 and E-selectin) expression concomitant with a significant inhibition in HMGB1-stimulated leukocyte-endothelial adhesion. Further experiments showed that atorvastatin markedly suppressed HMGB1-induced Toll like receptor 4 (TLR4) expression, Nuclear factor kappaB (NF-κB) nuclear translocation and DNA binding activity in ECs. Similar effects were also observed in ECs pretreated with the TLR4- specific inhibitor CLI-095, suggesting an important role of TLR4/NF-κB pathway. These findings indicate that atorvastatin attenuates HMGB1-induced vascular endothelial activation. The underlying mechanism involves, at least in part, inhibition of TLR4/NF-κB-dependent signaling pathway, which provied the new evidence for therapeutic application of statins to target inflammatory processes in cardiovascular disease.

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Acknowledgements

This work was supported by the Natural Science Foundation of Hubei province, China (Grant No. 2008CDZ044) and the Education Foundation of Hubei Province, China (Grant No. B20081303).

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China

    Jun Yang, Congxin Huang, Jian Yang & Hong Jiang

  2. Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Yichang, 443000, Hubei Province, China

    Jiawang Ding

Authors
  1. Jun Yang
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  2. Congxin Huang
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  3. Jian Yang
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  4. Hong Jiang
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  5. Jiawang Ding
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Corresponding author

Correspondence to Congxin Huang.

Additional information

Jun Yang and Jian Yang are Contributed equally to this work.

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Yang, J., Huang, C., Yang, J. et al. Statins attenuate high mobility group box-1 protein induced vascular endothelial activation : a key role for TLR4/NF-κB signaling pathway. Mol Cell Biochem 345, 189–195 (2010). https://doi.org/10.1007/s11010-010-0572-9

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