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Open Access Highly Accessed Research article

The role of p21-activated kinase in the initiation of atherosclerosis

K A Jhaveri1, P Debnath1, J Chernoff2, J Sanders1 and M A Schwartz13*

Author Affiliations

1 Department of Microbiology, University of Virginia, Cardiovascular Research Center, Charlottesville, Virginia, USA

2 Division of Oncology Research, Fox Chase Cancer Center, Buckingham, Pennsylvania, USA

3 Yale Cardiovascular Research Center, 300 George St., New Haven, CT 06511, USA

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BMC Cardiovascular Disorders 2012, 12:55  doi:10.1186/1471-2261-12-55

Published: 23 July 2012

Abstract

Background

p21-activated kinase (PAK) has been implicated in the inflammatory activation of endothelial cells by disturbed fluid shear stress, which is the initiating stimulus in atherosclerosis. The study addresses whether PAK1 contributes to inflammatory marker expression in endothelial cells at atherosclerosis-susceptible regions of arteries in vivo.

Method

Aortas from WT and PAK1-/- C57BL/6J mice on a normal chow diet were fixed, dissected and processed for immunohistochemistry using a panel of inflammatory markers. We visualized and quantified staining in the endothelium at the greater and lesser curvatures of the arch of aorta, as atherosclerosis-resistant and susceptible regions, respectively.

Results

Fibronectin, VCAM-1 and the activated RelA NF-κB subunit were localized to the lesser curvature and decreased in PAK1-/- mice. The activated RelB NF-κB subunit was also localized to the lesser curvature but was increased in PAK1-/- mice. Low levels of staining for ICAM-1 and the monocyte/macrophage marker Mac2 indicated that overall inflammation in this tissue was minimal.

Conclusion

These data show that PAK1 has a significant pro-inflammatory function at atherosclerosis-prone sites in vivo. These effects are seen in young mice with very low levels of inflammation, suggesting that inflammatory activation of the endothelium is primarily biomechanical. Activation involves NF-κB, expression of leukocyte recruitment receptors and fibronectin deposition. These results support and extend in vitro studies demonstrating that PAK contributes to activation of inflammatory pathways in endothelial cells by fluid shear stress.

Keywords:
Fluid shear stress; Endothelial cells; Vascular inflammation; Fibronectin