Molecular mechanisms in Abdominal Aortic Aneuysm

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DESCRIPTION (provided by applicant): Abdominal aortic aneurysm is a common age related and potentially lethal disease that develops as the result of a complex interplay among chronic inflammation, extracelluar matrix (ECM) degradation, and impaired ECM biosynthesis associated with depletion of medial smooth muscle cells (SMCs). However, the precise role of medial SMCs in this intricate network has yet to be elucidated. Results from our preliminary studies suggest that the signaling molecule protein kinase C-delta (PKC4) is upregulated in SMCs of human and animal aneurismal tissues. Using the CaCl2 model of aneurysm, we demonstrated that PKC4 gene deficient mice are protected from the development of aneurysms. Preliminary histological analyses indicate that PKC4 gene deficiency impairs infiltration of macrophages and prevents depletion of medial SMCs and degradation of ECM. These preliminary findings are novel and for the first time implicate PKC4 in the pathogenesis of aneurysms. We speculate that PKC4 might be an integral factor responsible for the apoptotic and pro-inflammatory behavior of SMCs associated with aneurysm. In this study, we propose three specific aims to test the hypothesis that PKC4 is an important molecular factor contributing to medial SMC depletion and vascular inflammation. The pro-inflammatory function of PKCd is mediated through monocyte chemoattactant protein-1 (MCP-1). In Specific Aim I, we will confirm the aneurysm-resistant phenotype of PKC4 knockout mice through the use of the CaCl2 model paired with a serial of histological analyses over the course of aneurysm development. In addition, we will test the role of PKC4 using the elastase perfusion model that induces aneurysm through a different mechanism. In Specific Aim II, we will delineate mechanisms through which PKC4 gene deficiency impairs aneurysm formation. First, we will test a new paradigm underlying MCP-1 gene expression involving Rho GTPase Cdc42 and MAP kinase ERK. Second, we will test whether restoring MCP-1 in the aortic wall rescues the impaired aneurysm in PKC4 knockout mice. Third, we will assess the role of PKC4 in macrophages and the potential contribution of inflammatory cells to the aneurysm resistant phenotype of PKC4 null mice. In Specific Aim III, we will characterize two peptide inhibitors of PKC4, one of which was developed during our preliminary studies, in order to develop a molecular reagent to antagonize PKC4 in vivo. The potential efficacy of the selected inhibitor to attenuate aneurysm development will be determined using the CaCl2 model. We believe that arterial PKC4 upregulation exemplifies an intracellular signaling network within SMCs that drives pro-inflammatory signaling and apoptosis. Through the proposed in vivo and in vitro studies, we will gain a better understanding of medial SMCs in the pathogenesis of abdominal aortic aneurysm, which will allow us to make contributions toward the development of novel therapies for this devastating vascular disease. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is a common degenerative disease associated with high mortality. Each year thousands of aneurysms, the majority of which are small, are identified through screening programs. Without treatment, these small aneurysms will enlarge and eventually rupture. Surgical repair is an effective approach to prevent deaths or complications resulting from a ruptured aneurysm, however, many patients with ruptured AAAs die before reaching a hospital. Therefore, there is a great need for alternative therapeutic strategies. By providing new information on regulatory mechanisms underlying smooth muscle cell apoptosis and inflammatory signaling, the proposed studies will further our understanding of the molecular mechanisms underlying the pathophysiology of aneurysms and facilitate development of novel therapeutic strategies aimed at slowing or reversing the growth of small aneurysms.