Regulation of Endothelial Inflammatory Responses by GPCRs

Smoking has been well established to affect the ability of blood vessels to function correctly. This creates a sustained disease state throughout the body called vascular inflammation and causes cardiovascular disease. Cardiovascular disease is the leading cause of death in the United States, and impacts over 61 million Americas each year. A properly functioning blood vessel cell has many tightly regulated proteins sending signals to turn on or off other proteins controlling different functions of the cell. Smoking has been shown to disrupt this cell signaling. This proposal examines one such pathway. However, to understand how this is affected by smoking, first, the mechanisms by which this cell signals in healthy conditions must be examined. The goal of this proposal is to understand how activation of a receptor in the blood vessels, specifically the protease-activated receptor-1 (PAR1), leads to vascular inflammation. We have previously shown the protein, p38 MAPK is activated by PAR1 and it is well established p38 MAPK is an important mediator of inflammation. Yet, how PAR1 signals via p38 MAPK to promote vascular pro-inflammatory responses remains poorly understood. The specific objective of this proposal is to elucidate the mechanisms by which p38 MAPK signaling induced by activated PAR1 promotes vascular inflammation. The proposed studies will determine if PAR1 activation of p38 functions through two proteins, MAPKAPK2 (MK2) and heat shock protein 27 (HSP27) to promote inflammatory responses. Both MK2 and HSP27 are shown to be turned on by p38 MAPK and have been shown to influence vascular inflammation. In preliminary studies, I found that both MK2 and HSP27 are turned on through a p38-dependent pathway following stimulation of PAR1 in endothelial (blood vessel specific) cells. The focus of the proposed studies will be to determine how PAR1 stimulated of MK2 and HSP27 regulate vascular inflammation by using both cell and animal models to assess this question. The contribution of this work is expected to be significant and will provide new information regarding a novel signaling pathway in blood vessels that modulates vascular inflammation and new strategies for targeted-drug development to control vascular inflammation. This includes, drug targets for the treatment of smoking-induced disruption of blood vessel signaling pathways mitigating the deleterious effects of sustained vascular inflammation on blood vessel function.