Laminar flow activation of ERK5 leads to cytoprotective effect via CHIP-mediated p53 ubiquitination in endothelial cells.
10.5115/acb.2011.44.4.265
- Author:
Jae Hyang LIM
1
;
Chang Hoon WOO
Author Information
1. Department of Biology and Center for Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA, USA.
- Publication Type:Original Article
- Keywords:
Laminar flow;
Endothelial apoptosis;
ERK5;
CHIP;
p53
- MeSH:
Apoptosis;
Atherosclerosis;
Endothelial Cells;
Inflammation;
Mitogen-Activated Protein Kinase 7;
Prostaglandin D2;
Transcription Factors;
Ubiquitin;
Ubiquitination
- From:Anatomy & Cell Biology
2011;44(4):265-273
- CountryRepublic of Korea
- Language:English
-
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-Delta(12,14)-prostaglandin J2 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.
