Nicotine and Abdominal Aortic Aneurysms
Initial Award Abstract
An abdominal aortic aneurysm (AAA) is defined as a pathologic expansion of aortic diameter > 30 mm near the level of the kidneys. AAAs are a significant cause of morbidity and mortality in the United States accounting for approximately 9,000-30,000 deaths and150,000 inpatient hospitalizations per year. Data from clinical studies suggest that the prevalence ranges 2.4-16.9% in men while it is 0.5-2.2% in women. Through increased awareness campaigns including a Pulitzer Prize winning series of AAA-related articles in the Wall Street Journal in 2004, tens of thousands of patients have come to realize that they have early AAA disease. For these “worried well” patients, whose aneurysms grow at a known and inexorable rate, there are no known effective treatments.
Other than age, male sex and family history, the most important risk factor for AAA development is history of tobacco use. The relative risk of AAA in individuals who have ever smoked is 2.5 times greater than the relative risk for coronary heart disease. Indeed, AAA is more closely associated with cigarette smoking than any other tobacco-related disease except lung cancer. Nearly all AAA patients (>90%) relate a history of smoking. In addition, several small studies have associated continued cigarette smoking with more rapid aneurysm expansion. However, at the time of AAA diagnosis, only half the number of patients with reported history of smoking continues to smoke. Thus, it is imperative that we also understand the underlying mechanisms of how tobacco use initiates as well as exacerbates AAA disease.
Data derived from preclinical animal models indicates that the major underlying mechanisms in AAA disease are dysregulated extracellular matrix turnover and inflammation. However, there is currently a relative paucity of mechanistic data in the literature aimed at explaining the role of tobacco use in AAA development. In the current proposal we present preliminary data indicating that supplementation with nicotine increases vascular inflammation. In addition, we have documented a significant percentage of genes in the aorta is altered during AAA development. Thus, we hypothesize that coordinated gene expression panels or cassettes are regulated during AAA disease. MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that may offer this hierarchical level of gene regulation. Using in silico analysis, we have identified two vascular miRNAs (miR-29 and miR-146) that have significant potential to be involved with AAA disease. Through a series of in vitro and in vivo experiments, we propose to investigate the regulation of miR-29 and miR-146, and their effects on vascular extracellular matrix remodeling and proinflammatory gene expression. Moreover, we will manipulate their expression levels to confirm their effects in aneurismal gene expression. Finally, we will produce preliminary data regarding a wide array of miRNAs and their regulation of vascular gene expression in response to nicotine. Data generated from these studies will not only add to our understanding of how tobacco use enhances AAA disease, but will lay the groundwork for several avenues of research on how miRNAs regulate tobacco-related cardiovascular disease. In addition, individual or combinations of miRNAs are attractive targets for future therapeutic strategies. |