TGF-beta through Smad family signaling stabilizes abdominal aortic aneurysms

Tsai, Shirling

Abstract

Abdominal aortic aneurysm (AAA) is a significant medical problem with a high mortality. AAA's are the 10th leading cause of death in white men between the ages of 65 and 74. The medical management of intermediate-sized asymptomatic AAA's has important implications from a public health perspective. Studies have shown that in patients with asymptomatic aneurysms less than 5.5cm, there is no survival benefit for elective repair as compared to surveillance. The implications of a molecular therapy that retards or halts the progression to symptomatic aneurysm or aneurysm rupture are greatest with respect to this group of patients. The purpose of this proposal is to gain a better understanding of the molecular mechanisms underlying aneurysm development. The pathophysiology of AAA is complex and not fully understood, but recent developments have suggested that transforming growth factor-beta (TGF-b) may stabilize aneurysm growth. Our preliminary data as well as the literature suggest that many of the observed beneficial effects of TGF-b on aneurysms, such as increased extracellular matrix synthesis or decreased inflammatory cytokines, may be mediated by SmadS, a downstream signaling molecule for TGF-b. We hypothesize that SmadS plays a critical role in the TGF-b signaling cascade with respect to aneurysm growth and wall remodeling. The first part of the proposal will examine whether SmadS regulates the degradation of extracellular matrix (ECM), an important characteristic of aneurysm wall remodeling. Specifically, we will test whether SmadS mediates the inhibitory effect of TGF-b on matrix metalloproteinase-9 (MMP-9), an elastase and collagenase whose overexpression has been associated with aneurysm development. Results of these studies will not only further our knowledge of matrix regulation but also establish the therapeutic potential of SmadS as a crucial regulator of both matrix synthesis and degradation. The second part of the study will test the clinical relevance of our findings from part one through loss- and gain-of function experiments in a mouse AAA model. We will first test the necessity of SmadS in aneurysm development by studying aneurysms in SmadS deficient mice (SmadS -/- ApoE-/- double knockout mice). We will then study the effect of upregulating SmadS on aneurysm development and healing. Our study endpoints will focus on aneurysm size, elastin content and structure, histology, and MMP-9 and SmadS expression. ? ? ?