C-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis

Hera Chaudhury, Mustafa Zakkar, Joseph Boyle, Simon Cuhlmann, Kim Van Der Heiden, Le Anh Luong, Jeremy Davis, Adam Platt, Justin C. Mason, Rob Krams, Dorian O. Haskard, Andrew R. Clark, Paul C. Evans

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

Objective-Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree. Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites. Methods and Results-We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1, and MKP-1 mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1. Conclusion-Spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries.

Original languageEnglish
Pages (from-to)546-553
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume30
Issue number3
DOIs
Publication statusPublished - Mar 2010

Keywords

  • Apoptosis
  • Arterial endothelium
  • Atherosusceptibility
  • C-Jun N-terminal kinase
  • Mitogen-activated protein kinase phosphatase-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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