The functions of big mitogen activated protein kinase 1 in endothelial cells

Endothelium, a single layer aligning all the blood vessels, controls many important functions including regulation of vascular tone, inflammation and coagulation. Derangements in endothelial function contribute to pathophysiological conditions such as hypertension and atherosclerosis. Mitogen activated protein kinases (MAPKs) are well-known to regulate gene expression, growth, differentiation and development and are important for maintenance of endothelial function. Big mitogen activated protein kinase 1 (BMK1, also called ERK5), one of MAPK family members, is expressed abundantly and is activated by growth factors and stress, in endothelial cells fluid shear stress is the strongest stimulus for BMK1. The contribution of BMK1 for endothelial function is unknown. We proposed that BMK1 plays important roles in the atheroprotective function of fluid shear stress and the regulation of angiogenesis. First, we demonstrated that BMK1 protects endothelial cells from apoptosis induced by growth factor deprivation and incubation with pro-inflammatory stimuli, and BMK1 is an important mediator for the anti-apoptotic effect of steady fluid shear stress. This protective function mediated by BMK1 contributes to the atheroprotective properties of the endothelium. The anti-apoptotic mechanism of shear stress and BMK1 activation likely involves phosphorylation of Bad on Ser 136 and Ser 112. Second, we found that BMK1 is a novel regulator of hypoxia inducible factor (HIF) 1alpha and angiogenesis by increasing HIF1alpha ubiquitination and degradation, as well as inhibiting HIF1alpha activity in EC. The negative regulation of HIF1alpha activity by BMK1 is suggested to be part of a feedback mechanism that decreases HIF1alpha activity induced by hypoxia. Third, the understanding of the functions of BMK1 in endothelium in vivo will be facilitated by successful production of two mouse lines: BMK1flox mouse which produces inducible endothelial-specific BMK1 knockout after cross with Tie2-CreER mouse, and Tie2-CA-MEK5 transgenic mouse which contains activated BMK1 in endothelium specifically. In conclusion, we found that BMK1 plays an important role in anti-apoptotic function of fluid shear stress and regulates HIF and angiogenesis, which may provide new therapeutic approaches for atherosclerosis and cancer.