DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease of primarily older patients. While surgery and stent-grafting are highly effective in preventing death by rupture from larger AAA, they represent complex procedures with multiple potential complica-tions. Importantly, there are currently no therapeutic strategies that limit the growth of aneurysms, due in large part to a lack of understanding of the underlying molecular mechanisms of disease and progression. In addition to tobacco use, genetic predilection, and male sex, the most important risk factor for AAA is advanced age. As such, it is not surprising that over 68,000 Veterans within the VHA suffer from AAA. After age 65 years, the prevalence of AAA increases by 6% per decade. To better understand this relationship, we examined a preclinical animal model of AAA in both young and aged male mice, and observed accelerated disease formation and enhanced interleukin-6(IL6)- based inflammatory signaling with aging. We also found that miR-24 is downregulated in murine AAA models, as well as human AAA tissue. Furthermore, microarray transcriptional profiling showed that a highly significant percentage of the putative targets of miR-24 were differentially and inversely upregulated during AAA development. Additionally we found that miR-24 is downregulated by IL6 in vascular smooth muscle and macrophages in vitro. We hypothesize aging enhances IL6 signaling, leading to downregulation of vascular miR-24. Reduced activity of miR-24, in turn, is permissive for a panel of downstream inflammatory genes that play a role in aging-accelerated AAA development. Therefore, enhancing miR-24 expression and activity within the aortic wall may have therapeutic benefit. To investigate this molecular cascade, we will use pharmacological and molecular methods to delineate the signaling events initiated by IL6 in vitro that result in decreased miR-24 levels (Specific Aim 1). Next, we will elucidate the effects manipulating miR-24 levels have upon inflammatory gene expression and cellular function (Specific Aim 2). Finally, we will alter miR-24 levels in vivo to evaluate the effects upon age-accelerated AAA formation (Specific Aim 3). Completion of these specific aims will delineate a novel mechanism that may underlie age-related vascular inflammation and accelerated aneurysm formation and provide the basis for clinical translation.

PUBLIC HEALTH RELEVANCE: Relevance of the proposed research to Veterans' health: Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease of primarily older patients. Importantly, there are currently no therapeutic strategies that limit the growth of aneurysms, due in large part to a lack of understanding of the underlying molecular mechanisms of disease and progression. Since the risk factors for AAA include advanced age, male sex, and tobacco use, it is not surprising that over 68,000 Veterans within the VHA suffer from AAA. Our preliminary data indicates that advanced age is associed with enhanced vascular inflammation and abdominal aortic aneurysm (AAA) disease in preclinical animal models in association with decreased microRNA-24. We proposed to use a combination of molecular and physiological models to clarify the underlying mechanism of how miR-24 can regulate AAA formation. The success of the proposed studies could lead to novel therapeutic approaches to prevent development and/or limit progression of AAA disease.