| First Author | Mylroie H | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 106 |
| Issue | 3 | Pages | 509-19 |
| PubMed ID | 25883219 | Mgi Jnum | J:258774 |
| Mgi Id | MGI:6121001 | Doi | 10.1093/cvr/cvv131 |
| Citation | Mylroie H, et al. (2015) PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis. Cardiovasc Res 106(3):509-19 |
| abstractText | 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. |
