Atherosclerosis Studied At The Cellular Level

Richard Austin, PhD, and a team of researchers are studying the cellular and molecular mechanisms that accelerate the development and progression of atherosclerosis, the underlying cause of cardiovascular disease and stroke. These studies have provided important clues as to how changes in cell function contribute to this progressive and life threatening disease.

Dr. Austin, a professor in the department of Pathology and Molecular Medicine and a Career Investigator of the Heart and Stroke Foundation of Ontario, said the study found that nitric oxide, normally considered a "good player" in protection against atherosclerosis, could sometimes be converted into a toxic byproduct with a detrimental impact on cell viability and function.

"The results from our study show that under the right cellular conditions, such as the increased production of cellular oxidants, nitric oxide can be converted into a very "bad player", namely peroxynitrite," said Dr. Austin, a Staff Scientist who works at the Henderson Research Centre.

"Although previous reports have demonstrated that the generation of peroxynitrite in the vessel wall accelerates atherosclerosis, the cellular mechanism responsible for this effect was relatively unknown. Our study shows that the production of peroxynitrite causes cell dysfunction and death by activating or 'turning on' a cellular stress pathway, termed the ER stress response pathway.

Although activation of this pathway is considered to be protective, prolonged or severe ER stress induced by peroxynitrite can lead to devastating cytotoxic effects. In addition to these findings, we have reported previously that activation of this cellular stress pathway causes changes in lipid metabolism and inflammation, conditions that also accelerate atherosclerosis."

Based on these findings, Dr. Austin and his research team are now developing novel strategies to block this cellular stress pathway in the hopes of inhibiting cell dysfunction and death, which can ultimately lead to the development of atherosclerosis and cardiovascular disease.

Dr. Austin also presented this work at a recent international meeting in Japan in which he was the only Canadian researcher to be invited to speak.

Lead author on the December cover article is Dr. Jeffrey Dickhout, a recipient of a Heart and Stroke Foundation of Ontario Post-Doctoral Fellowship. Other McMaster researchers involved in the project are Gazi Hossain, Lindsay Pozza, Ji Zhou, and Šárka Lhoták These studies were supported by both the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research.