Grant: Project Grant

In the last several years the applicants have identified that lipid-derived factors play a major role in the development of calcific aortic stenosis (AS). AS is one of the most prevalent cardiovascular disorder and there is, for the time being, no medical treatment that could stop its progression. When AS is severe the aortic valve must be replaced by using an open heart surgery or by a percutaneous approach. These interventions are associated with a significant morbidity/mortality rate and are costly for the health care system. Therefore, further investigation is needed to understand the basic processes underlying the development of AS. Our group has identified that a group of lipid, which are oxidized are present in the aortic valve and promote the mineralization of the tissues, a major culprit in AS. Specifically, we have documented that one enzyme, autotaxin (ATX), produces lysophosphatidic acid (LPA), which in turn promote inflammation and aortic valve mineralization. In the next several years, by using different approaches we will determine the mechanisms whereby ATX and LPA promote the development of AS. Furthermore, we will test in a mouse model the role of ATX-LPA signaling in the aortic valve and test the hypothesis that it plays a major role into the development of this disorder. Hence, this work will provide important novel insights about the molecular mechanisms that drive the development of AS and may help design novel form of pharmaceutical therapies.