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Anatomy & cell biology

Laminar flow activation of ERK5 leads to cytoprotective effect via CHIP-mediated p53 ubiquitination in endothelial cells.


PMID 22254155

Abstract

Atherosclerosis is readily observed in areas where disturbed flow is formed, while the atheroprotective region is found in areas with steady laminar flow (L-flow). It has been established that L-flow protects endothelial cells against endothelial dysfunction, including apoptosis and inflammation. It has also been reported that extracellular signal-regulated kinase 5 (ERK5) regulated endothelial integrity and protected endothelial cells from vascular dysfunction and disease under L-flow. However, the molecular mechanism by which L-flow-induced ERK5 activation inhibits endothelial apoptosis has not yet been determined. Transcription factor p53 is a major pro-apoptotic factor which contributes to apoptosis in various cell types. In this study, we found that 15-deoxy-Δ(12,14)-prostaglandin J(2) induced p53 expression and that endothelial apoptosis was reduced under the L-flow condition. This anti-apoptotic response was reversed by the biochemical inhibition of ERK5 activation. It was also found that activation of ERK5 protected endothelial apoptosis in a C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase-dependent manner. Moreover, molecular interaction between ERK5-CHIP and p53 ubiquitination were addressed with a CHIP ubiquitin ligase activity assay. Taken together, our data suggest that the ERK5-CHIP signal module elicited by L-flow plays an important role in the anti-apoptotic mechanism in endothelial cells.