Abstract 14415: The Sumo Protease Senp2 Regulates Endothelial Dysfunction and Subsequent Atherosclerosis Formation
Background- It has been well established that disturbed flow (d-flow) induces the proinflammatory and apoptotic responses, causing them to become dysfunctional and subsequently pro-atherogenic. SUMOylation which, in addition to other vaious effects, can alter the localization and transcriptional activity of certain proteins has emerged as an important regulatory mechanism for intracellular signaling. Although we have reported that d-flow increases endothelial apoptosis via p53 SUMOylation, the role of SUMOylation in the d-flow-mediated ECs dysfunction and subsequent atherosclerosis remains largely unknown.
Methods and Results- Here, we show the crucial role of sentrin/SUMO-specific protease 2 (SENP2) in d-flow-mediated SUMOylation of p53 and ERK5. SENP2 inhibited d-flow-induced endothelial apoptosis and inflammation by up regulating SUMOylation of p53 and ERK5, respectively. Increased atherosclerosis lesions were observed in heterozygous SENP2+/- mice with the low density lipoprotein receptor null LDLR-/- background (SENP2+/-/LDLR-/-) on a high cholesterol diet . Indeed, increased endothelial apoptosis and enhanced expression of pro-inflammatory genes were observed in SENP2+/- mice. Bone marrow transfer experiments in which LDLR-/- mice were transplanted with bone marrow cells from SENP2+/- or wild type mice did not show different atherosclerotic incidences, suggesting that the enhanced atherosclerosis formation observed in SENP2+/-/LDLR-/- mice is of vascular origin.
Conclusions- These data show the unique role of SENP2 on EC function under the d-flow condition and provide the evidence that SUMOylaltion of p53 and ERK5 mediate pro-atherogenic effects, which may be useful targets for the treatment of EC dysfunction and subsequent atherosclerosis formation.
- © 2012 by American Heart Association, Inc.