Macrophage Pyroptosis in Abdominal Aortic Aneurysm

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Project Summary The purpose of this K99/R00 application is to (1) provide me with necessary training in research and career development for my transition to a successful independent researcher; (2) study the role of pyroptosis, a novel form of programmed cell death, in the rupture of Abdominal Aortic Aneurysm (AAA). AAA is a progressive pathological dilation and weakening of the aorta. AAA is associated with extreme rates of death (up to 80%) in the event of aortic rupture. There has no medical therapy to prevent or treat aortic rupture, which is largely attributed to that mechanisms underlying AAA rupture have not been defined. AAA is characterized by inflammation and frequent presence of thrombus. Inflammatory lesions often contain dead cells. Until recently, programmed cell death was thought to occur only in one form, called “apoptosis”. In 2015 and 2016, four Nature publications from three groups revealed gasdermin D (GSDMD)-dependent mechanisms of pyroptosis. GSDMD forms pores on cell surface and ruptures cell membrane. In ruptured cell membrane, phosphatidylserine, which is exclusively located in the inner monolayer in living cells, freely flip into outer monolayer and forms a procoagulant surface for tissue factor by facilitating the assembly of proteins of clotting cascade. We recently discovered that macrophage pyroptosis caused septic death through tissue factor release, which triggered disseminated intravascular coagulation in mice. My preliminary data show that genetic deficiency of GSDMD protects against AAA rupture in angiotensin II-infused mice. In this proposal, I will test the hypothesis that macrophage pyroptosis promotes AAA rupture through tissue factor-dependent thrombus propagation. Two aims will be addressed to test this hypothesis. In Aim 1, I will profile macrophage pyroptosis in angiotensin II-induced AAA rupture using caspase-1 and Caspase-11 deficient mice (K99 PHASE). In Aim 2, I will determine how macrophage pyroptosis, through tissue factor-mediated mechanisms, contributes to AAA rupture (R00 PHASE). Together I will examine the causal relationship between thrombus and AAA rupture and test the concept of a feedforward loop between macrophage pyroptosis and tissue factor/thrombus until AAA rupture. This project is important because GSDMD and pyroptosis may represent a therapeutic target. This project is innovative because it defines a novel procoagulant mechanism in AAA. I will also examine macrophage biology and pyroptosis in human aortic aneurysm tissues available in Dr. LeMaire’s Aortic Disease Biobank at Baylor College of Medicine to enhance the translational aspects of my proposed research.