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. In addition to advanced age, genetic predilection, and male sex, the most important risk factor for AAA is a history of tobacco use. We have found that supplementation of two preclinical animal models of AAA with the major tobacco component, nicotine, causes accelerated disease formation and enhanced inflammatory signaling. These effects are associated with downregulation of microRNA (miR)-24. Given that many of its gene targets are pro-inflammatory, miR-24 is a prime suspect in the chronic inflammation and accelerated AAA development associated with nicotine supplementation and may, therefore, offer a therapeutic target. We hypothesize that nicotine causes downregulation of aortic miR-24, resulting in elevated expression of genes related to inflammation and accelerated AAA disease. Conversely, enhancing miR-24 expression and activity within the aortic wall will have therapeutic benefit.
In Specific Aim 1, we will use cell culture models as well as pharmacological and molecular methods to delineate the signaling events initiated by nicotine that result in decreased miR-24 levels.
In Specific Aim 2, we will determine the downstream effects of reduced miR-24 on inflamamtiory gene expression and cellular function. Finally, in Specific Aim 3, we will modulate miR-24 levels in vivo to evaluate the effects upon AAA formation.
These specific aims will investigate a novel mechanism that may underlie nicotine-induced vascular inflammation and accelerated aneurysm formation as well as provide the basis for advancing future research and clinical translation.
Our preliminary data indicates that the major tobacco component, nicotine, enhances 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.
|Maegdefessel, Lars; Spin, Joshua M; Tsao, Philip S (2014) New ways to dismantle a ticking time bomb: microRNA 712/205 and abdominal aortic aneurysm development. Arterioscler Thromb Vasc Biol 34:1339-40|
|Spin, Joshua M; Tsao, Philip S (2014) Battle of the bulge: miR-195 versus miR-29b in aortic aneurysm. Circ Res 115:812-3|
|Maegdefessel, Lars; Spin, Joshua M; Raaz, Uwe et al. (2014) miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat Commun 5:5214|