Statins attenuate high mobility group box-1 protein induced vascular endothelial activation : a key role for TLR4/NF-κB signaling pathway
- 17 August 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular and Cellular Biochemistry
- Vol. 345 (1-2), 189-195
- https://doi.org/10.1007/s11010-010-0572-9
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.Keywords
This publication has 35 references indexed in Scilit:
- Response of macrophage Toll‐like receptor 4 to a Sporothrix schenckii lipid extract during experimental sporotrichosisImmunology, 2009
- Intercellular Adhesion Molecule-1–Dependent Neutrophil Adhesion to Endothelial Cells Induces Caveolae-Mediated Pulmonary Vascular HyperpermeabilityCirculation Research, 2008
- Bacterial lipopolysaccharide induces increased expression of toll-like receptor (TLR) 4 and downstream TLR signaling molecules in bovine mammary epithelial cellsVeterinary Research, 2007
- Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damagesJournal of Applied Physiology, 2007
- TNFR1-induced NF-κB, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cellsCellular Signalling, 2007
- Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 AdenovirusCirculation Research, 2006
- The Effects of Statins on Endothelium, Inflammation and CardioprotectionDrug News & Perspectives, 2005
- Silymarin inhibits TNF‐α‐induced expression of adhesion molecules in human umbilical vein endothelial cellsFEBS Letters, 2003
- Release of chromatin protein HMGB1 by necrotic cells triggers inflammationNature, 2002
- In Vivo Expression of Proinflammatory Mediators in the Adult Heart after Endotoxin Administration: The Role of Toll‐Like Receptor–4The Journal of Infectious Diseases, 2001