Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis

Mustafa Zakkar, Hera Chaudhury, Gunhild Sandvik, Karine Enesa, Le Anh Luong, Simon Cuhlmann, Justin C. Mason, Rob Krams, Andrew R. Clark, Dorian O. Haskard, Paul C. Evans

Research output: Contribution to journalArticlepeer-review

79 Citations (Scopus)

Abstract

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.

Original languageEnglish
Pages (from-to)726-732
Number of pages7
JournalCirculation Research
Volume103
Issue number7
DOIs
Publication statusPublished - 26 Sept 2008

Keywords

  • Atherosclerosis
  • Endothelial cells
  • MAP kinase phosphatase-1
  • MAP kinases
  • Shear stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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