RATIONALE: Disturbed flow induces proinflammatory and apoptotic responses in endothelial cells, causing them to become dysfunctional and subsequently proatherogenic.
OBJECTIVE: Although a possible link between SUMOylation of p53 and ERK5 detected during endothelial apoptosis and inflammation has been suggested, the mechanistic insights, especially under the proatherogenic flow condition, remain largely unknown.
METHODS AND RESULTS: SUMOylation of p53 and ERK5 was induced by disturbed flow but not by steady laminar flow. To examine the role of the disturbed flow-induced p53 and ERK5 SUMOylation, we used de-SUMOylation enzyme of sentrin/Small Ubiquitin-like MOdifier (SUMO)-specific protease 2 deficiency (Senp2(+/-)) mice and observed a significant increase in endothelial apoptosis and adhesion molecule expression both in vitro and in vivo. These increases, however, were significantly inhibited in endothelial cells overexpressing p53 and ERK5 SUMOylation site mutants. Senp2(+/-) mice exhibited increased leukocyte rolling along the endothelium, and accelerated formation of atherosclerotic lesions was observed in Senp2(+/-)/Ldlr(-/-), but not in Senp2(+/+)/Ldlr(-/-), mice fed a high-cholesterol diet. Notably, the extent of lesion size in the aortic arch of Senp2(+/-)/Ldlr(-/-) mice was much larger than that in the descending aorta, also suggesting a crucial role of the disturbed flow-induced SUMOylation of proteins, including p53 and ERK5 in atherosclerosis formation.
CONCLUSIONS: These data show the unique role of sentrin/SUMO-specific protease 2 on endothelial function under disturbed flow and suggest that SUMOylation of p53 and ERK5 by disturbed flow contributes to the atherosclerotic plaque formation. Molecules involved in this newly discovered signaling will be useful targets for controlling endothelial cells dysfunction and consequently atherosclerosis formation.
- Bone Marrow Transplantation
- Cell Adhesion Molecules
- Endothelial Cells
- Endothelium, Vascular
- Kruppel-Like Transcription Factors
- Mice, Inbred C57BL
- Mitogen-Activated Protein Kinase 7
- Nitric Oxide Synthase Type III
- Protein Processing, Post-Translational
- SUMO-1 Protein
- Small Ubiquitin-Related Modifier Proteins
- Tumor Suppressor Protein p53
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't