Regulation of mitogen-activated protein kinase (MAPK) activity by AMP-activated protein kinase (AMPK) in endothelial cells

Atherosclerosis (narrowing or “furring up” of the arteries) is the main cause of heart disease and stroke. In healthy people, the cells that line blood vessels (endothelial cells) maintain cardiovascular health yet this beneficial action is lost in response to a variety of factors, such as high blood pressure, obesity and diabetes. We have previously shown that a protein called “AMPK” can block this switch from a healthy to diseased endothelium. Furthermore, we have shown that AMPK reduces the activity of important cellular proteins called “MAPKs” which are activated in the early stages of atherosclerosis by a mechanism that is currently unknown. This proposal seeks to understand the mechanisms by which AMPK inhibits MAPKs in human endothelial cells cultured in the laboratory. By identifying processes that limit MAPK activation in the endothelium, we will not only determine how AMPK activation may limit cardiovascular disease but may also identify new targets for more effective drugs