P. gingivalis (Pg) is not only a pathogen in periodontitis but is also an etiological agent of a variety of extraoral infections and is implicatd in the initiation and/or progression of atherosclerosis (ACD). Cardiovascular endothelial cells are key to the initiation and progression of cardiovascular diseases (CVDs) such as ACD. Pg can invade various types of endothelial cells and causes dysfunction of these cells, resulting in a response by the endothelial cells that is similar to that known to occur in human ACD, especially the stimulation of multiple effectors via the innate immune pathways. There is no question that both inflammation and autophagy contribute to ACD. Pg stimulation of the classic inflammatory pathways in ACD has been well investigated. However the contribution and mechanism of Pg mediated disruption of endothelial autophagy on endothelial dysfunction/ACD has not been elucidated. Recent work by our group suggests that high jacking of the autophagic pathway by Pg is an important mechanism that promotes endothelial dysfunction which results in pro-inflammatory responses, increased oxidative stress, and/or programmed cell death. This results in an inability of the host cells to adequately respond to stress, causing cell death. We hypothesize that the mechanism by which Pg manipulates endothelial autophagy disrupts the endothelial cell's ability to use autophagy as a means of restoring homeostasis during oxidative or hyperlipidemic stress, resulting in endothelial dysfunction and, ultimately, ACD. The objective of this application is to employ both in vitro and in vivo approaches to investigate this hypothesis. We propose to compare the effects of a Pg strain able to usurp autophagy and an isogenic mutant that cannot on endothelial cell dysfunction and extent of ACD, whether or not this mechanism occurs independently of proinflammatory responses triggered by innate immune signaling, and determine if drugs that turn on or off autophagy rescue the host cell from Pg induced dysfunction. Given the similarities of endothelial dysfunction in ACD and periodontitis, we expect that many of the results of these studies would also relate to endothelial cells and oral disease.
This project is designed to investigate how a bacterium from the mouth that is proposed to also be involved in atherosclerosis causes or makes atherosclerosis worse. We also propose to test potential drugs that may prevent the bacterium from participating in the disease process.
