Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526289
Title: c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis
Author: Chaudhury, Hera Ashraf
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Abstract:
Atherosclerosis can be initiated by pro-inflammatory activation of endothelial cells (EC) which leads to the recruitment of leukocytes to the vessel wall, and also by endothelial apoptosis which elevates the permeability of arteries to lipoproteins. The greater curvature of the aorta is exposed to high shear and is protected from EC apoptosis, inflammation and atherosclerosis, whereas the lesser curvature is exposed to low shear and is susceptible to atherosclerosis. Pro-inflammatory mediators (e.g. TNFα, LPS) trigger phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAP kinases to positively regulate these process and influence atherosclerosis. I examined the effects of JNK activation on EC physiology at atherosusceptible sites. En face staining revealed that phosphorylation of JNK in EC occurs constitutively at the susceptible site of the murine aortic arch and can be enhanced by LPS treatment. In contrast, JNK activation was suppressed at the protected site by mitogen-activated protein kinase phosphatase-1 (MKP-1), a negative regulator of JNK and p38 MAP kinases. To study the function of JNK and p38 in vascular endothelium, I identified the transcriptional programs that they regulate by applying specific pharmacological inhibitors to cultured EC and assessing the transcriptome using microarrays. Functional annotation revealed that JNK and p38 positively regulate the expression of numerous pro-inflammatory and pro-apoptotic molecules. Subsequent gene silencing studies demonstrated that JNK1 positively regulates pro-apoptotic molecule expression in EC. I validated my findings in vivo by analyzing EC in aortae of wild-type, JNK1-/- and MKP-1-/- mice. I observed that EC at an atherosusceptible site express pro-apoptotic proteins and are primed for apoptosis and proliferation in response to LPS through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of pro-apoptotic molecules and was protected from injury by MKP-1. These findings indicate that the spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries, and may influence the punctuate development of atherosclerotic lesions.
Supervisor: Evans, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.526289  DOI: Not available
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