Recent estimates indicate that 5-10% of men and 1-2% of women 65-79 years of age in the United States are living with an abdominal aortic aneurysm (AAA). Approximately 15,000 will die each year due to AAA rupture. The treatment for AAA is limited to surgical intervention due to lack of other therapies with proven benefit. Although most patients with AAAs are asymptomatic, the risk of death due to rupture increases greatly as AAAs expand. Insights into mechanisms contributing to AAA progression would have a major impact on the clinical management of AAA by providing new biomarkers that predict AAA expansion and thus the risk for aortic rupture, as well as novel strategies for intervention. Recent published findings from our laboratory provide the impetus for a detailed evaluation of serum amyloid A (SAA) in AAA progression: 1) SAA deficiency attenuates AAA in a mouse model; 2) in mice, SAA is present in AAA in regions with substantial elastin degradation, macrophage infiltration, and matrix metalloproteinase (MMP) activity; and 3) SAA can be detected in human AAA. In unpublished work, we also determined that SAA induces IL-1? and NLRP3 expression, as well as IL-1? secretion, in macrophages, consistent with priming and activation of the NLRP3 inflammasome. These findings are notable, given the recent recognition that NLRP3 inflammasome activation is a critical event in AAA development in mice. Thus, our central hypothesis is that SAA activates the NLRP3 inflammasome, thereby amplifying local inflammatory responses that enhance pathological tissue remodeling and promote AAA progression.
AIM 1 : Investigate the role of the NLRP3 inflammasome in SAA's ability to promote AAA in mice.
Aim 1 a. Using mice deficient in various inflammasome components (NLRP3-/-, ASC-/-, caspase-1-/- mice) or IL-1? signaling (IL-1R-/- mice), we will determine whether SAA-mediated AAA is dependent on the NLRP3 inflammasome. We will also investigate whether small-molecule anionic sulphonates, a treatment that blocks the deposition of SAA in tissues, is effective in reducing AAA in mice.
Aim 1 b. Using macrophage cell cultures, we will investigate whether any of the known biological activities attributed to SAA, including reactive oxygen species generation or association with HDL, are involved in SAA-mediated NLRP3 inflammasome activation.
AIM 2 : To test the hypothesis that systemic SAA promotes the progression of an established AAA.
Aim 2 a. Our approach will be to transiently increase SAA expression in livers of mice at specific intervals during the course of AngII infusion through the use of viral vectors and an inducible transgene. As a complementary approach, SAA expression will be suppressed using antisense oligonucleotides. The impact of SAA on indices of AAA progression and aortic inflammation and remodeling will be determined.
Aim 2 b. To investigate the potential role of SAA and inflammasome activation in human AAA, the relationship between plasma SAA, IL-1? and the rate of AAA expansion in humans will be determined in the prospective N-TA3CT trial. These studies hold the potential for identifying new strategies for the clinical management of AAA.
Approximately 15,000 people in the United States alone die every year due to rupture of an abdominal aortic aneurysm (AAA). The clinical management of patients with AAA is challenged by the lack of effective treatments, and the fact that most patients with AAA do not exhibit symptoms. This project investigates whether serum amyloid A, a protein known to be involved in the normal response to infection and injury, may be useful for developing new approaches for the identification, care and management of patients with AAA.
|Thompson, Joel C; Wilson, Patricia G; Shridas, Preetha et al. (2018) Serum amyloid A3 is pro-atherogenic. Atherosclerosis 268:32-35|
|Shridas, Preetha; De Beer, Maria C; Webb, Nancy R (2018) High-density lipoprotein inhibits serum amyloid A-mediated reactive oxygen species generation and NLRP3 inflammasome activation. J Biol Chem 293:13257-13269|
|Wilson, Patricia G; Thompson, Joel C; Shridas, Preetha et al. (2018) Serum Amyloid A Is an Exchangeable Apolipoprotein. Arterioscler Thromb Vasc Biol 38:1890-1900|