PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis Journal Article

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Authors: Mylroie, H.; Dumont, O.; Bauer, A.; Thornton, C. C.; Mackey, J.; Calay, D.; Hamdulay, S. S.; Choo, J. R.; Boyle, J. J.; Samarel, A. M.; Randi, A. M.; Evans, P. C.; Mason, J. C.
Article Title: PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
Abstract: AIMS: Vascular injury leading to endothelial dysfunction is a characteristic feature of chronic renal disease, diabetes mellitus, and systemic inflammatory conditions, and predisposes to apoptosis and atherogenesis. Thus, endothelial dysfunction represents a potential therapeutic target for atherosclerosis prevention. The observation that activity of either protein kinase C epsilon (PKCepsilon) or haem oxygenase-1 (HO-1) enhances endothelial cell (EC) resistance to inflammation and apoptosis led us to test the hypothesis that HO-1 is a downstream target of PKCepsilon. METHODS AND RESULTS: Expression of constitutively active PKCepsilon in human EC significantly increased HO-1 mRNA and protein, whereas conversely aortas or cardiac EC from PKCepsilon-deficient mice exhibited reduced HO-1 when compared with wild-type littermates. Angiotensin II activated PKCepsilon and induced HO-1 via a PKCepsilon-dependent pathway. PKCepsilon activation significantly attenuated TNFalpha-induced intercellular adhesion molecule-1, and increased resistance to serum starvation-induced apoptosis. These responses were reversed by the HO antagonist zinc protoporphyrin IX. Phosphokinase antibody array analysis identified CREB1((Ser133)) phosphorylation as a PKCepsilon signalling intermediary, and cAMP response element-binding protein 1 (CREB1) siRNA abrogated PKCepsilon-induced HO-1 up-regulation. Likewise, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was identified as a PKCepsilon target using nuclear translocation and DNA-binding assays, and Nrf2 siRNA prevented PKCepsilon-mediated HO-1 induction. Moreover, depletion of CREB1 inhibited PKCepsilon-induced Nrf2 DNA binding, suggestive of transcriptional co-operation between CREB1 and Nrf2. CONCLUSIONS: PKCepsilon activity in the vascular endothelium regulates HO-1 via a pathway requiring CREB1 and Nrf2. Given the potent protective actions of HO-1, we propose that this mechanism is an important contributor to the emerging role of PKCepsilon in the maintenance of endothelial homeostasis and resistance to injury.
Journal Title: Cardiovascular research
Volume: 106
Issue: 3
ISSN: 1755-3245; 0008-6363
Publisher: . Published by Oxford University Press on behalf of the European Society of Cardiology  
Journal Place: England
Date Published: 2015
Start Page: 509
End Page: 519
Language: eng
DOI/URL:

10.1093/cvr/cvv131
Notes: LR: 20150528; CI: (c) The Author 2015; GR: Arthritis Research UK/United Kingdom; JID: 0077427; OID: NLM: PMC4431664; OTO: NOTNLM; 2014/11/06 [received]; 2015/04/03 [accepted]; 2015/04/16 [aheadofprint]; ppublish