Aortic aneurysms can occur in any location of the aorta, but most are found in the distal abdominal segment, hence, abdominal aortic aneurysm or AAA. AAA is more common in men, but rupture risk for small aneurysms is threefold higher in women. Ruptured aortic aneurysms account for 15,000 deaths/yr in the U.S. making AAA the 14th leading cause of death in men. The economic impact of studies and treatment of AAA exceeds a billion dollars per year. Importantly, AAA is the only cardiovascular disease for which there is no medical therapy. Known features of AAA include destruction of the lamellar architecture, increased levels of TNF-1 and IFN-3, and dense inflammation with a predominance of CD4+ T cells. CD4+ cells orchestrate the inflammatory process and matrix damage through secreted cytokines and macrophage recruitment. The two main subtypes of the CD4+ population are the T regulatory cell (Treg) and the T effector cell (Teff). The Teff cells drive an aggressive proinflammatory response that leads to significant matrix destruction, in part through their secretion of TNF-1 and IFN-3. Although small in proportion, the Treg cells exert an enormous counterbalance to Teff cells by 1) inhibiting Teff cell proliferation, 2) inhibiting secretion of TNF-1 and IFN-3 from Teff cells and macrophages, and 3) eliminating autoreactive T cells that may induce an autoimmune inflammatory process. We hypothesize that intrinsic difference in CD4+ T cells are responsible for susceptibility or resistance to aneurysm formation. The hypothesis is supported by preliminary data showing differences in circulating CD4+ cells from AAA patients and a matched control group. The hypothesis will be tested by studying circulating CD4+ cells isolated from AAA and matched control patients defining (Aim 1) differences in protein expression of key immunoregulatory cytokines (TNF-1, IFN-3, IL-2), (Aim 2) determining the effects of engrafting human CD4+ cells from AAA and control patients into a humanized murine model of AAA, (Aim 3) determining the proportion and function (inhibition of Teff cell proliferation or inhibition of Teff cell TNF-1, IFN-3 secretion) of circulating Treg cells from AAA and control patients, and (Aim 4) determining the effects of manipulating Treg cell number in a murine model of AAA.
These aims will be accomplished using molecular approaches, a defined study patient population, and a well characterized model of AAA that we can humanize by engrafting human CD4+ cells. AAA research is at an impasse with regard to identifying the basic causes of the disease. We believe the proposed work will identify the cell type that confers AAA susceptibility. Focusing future AAA research on a single cell type will greatly enhance the chances of finding the combination of gene products that cause AAA. The results of this study could have an immediate impact on patient care as evaluation of circulating CD4+ cells could identify AAA susceptible individuals before aneurysm or at the earliest stage of the disease.
Aortic aneurysm is a ballooning of the main blood vessel from the heart. If the aneurysm grows large enough, it requires operative repair in order to prevent rupture and death. There are many individuals with small aneurysms that are being watched for enlargement. The purpose of this proposal is to understand what makes aneurysms grow so that we can find medications to prevent growth and aneurysm rupture.
|Shimizu-Hirota, Ryoko; Xiong, Wanfen; Baxter, B Timothy et al. (2012) MT1-MMP regulates the PI3K?·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev 26:395-413|
|Xiong, Wanfen; Knispel, Rebecca; MacTaggart, Jason et al. (2009) Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo. J Biol Chem 284:1765-71|
|Xiong, Wanfen; MacTaggart, Jason; Knispel, Rebecca et al. (2009) Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol 183:2741-6|
|Xiong, Wanfen; Mactaggart, Jason; Knispel, Rebecca et al. (2009) Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model. Atherosclerosis 202:128-34|
|Xiong, Wanfen; Knispel, Rebecca A; Dietz, Harry C et al. (2008) Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome. J Vasc Surg 47:166-72;discussion 172|
|Baxter, B Timothy; Terrin, Michael C; Dalman, Ronald L (2008) Medical management of small abdominal aortic aneurysms. Circulation 117:1883-9|
|Xiong, Wanfen; Knispel, Rebecca; Mactaggart, Jason et al. (2006) Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation. J Vasc Surg 44:1061-6|
|Longo, G Matthew; Buda, Steven J; Fiotta, Nicola et al. (2005) MMP-12 has a role in abdominal aortic aneurysms in mice. Surgery 137:457-62|
|Xiong, Wanfen; Zhao, Yong; Prall, Amy et al. (2004) Key roles of CD4+ T cells and IFN-gamma in the development of abdominal aortic aneurysms in a murine model. J Immunol 172:2607-12|
|Longo, G Matthew; Xiong, Wanfen; Greiner, Timothy C et al. (2002) Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110:625-32|
Showing the most recent 10 out of 11 publications