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Underlying Mechanisms Regulating the Effects of Inhaled Nicotine upon Abdominal Aortic Aneurysm

Institution: Palo Alto Veterans Institute For Research
Investigator(s): Philip Tsao,
Award Cycle: 2019 (Cycle 29) Grant #: T29IR0636 Award: $1,044,000
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Research Project Award
Abstracts

Initial Award Abstract
Abdominal aortic aneurysm (AAA; weakening of the major artery from the heart) disease is a common, morbid and highly lethal disease of older individuals. In the United States, AAAs account for approximately 9,000-30,000 deaths and 150,000 inpatient hospitalizations per year. Current estimates are that AAA affects approximately 3% of women and 6% of men over the age of 65. 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. The most important modifiable risk factor for AAA development is history of tobacco use. Nearly all AAA patients (>90%) relate a history of smoking. Indeed, AAA is more closely associated with cigarette smoking than any other tobacco-related disease except lung cancer. In addition, several small studies have associated continued smoking with more rapid aneurysm expansion. However, to date, the molecular mechanisms underlying the relationship between smoking and AAA disease have been minimally explored; importantly, there is currently no information about the effects of e-cigarettes or other modes of inhaled nicotine. Given the popularity of e-cigarettes and vaping, especially with younger demographics, understanding the effects of their use on AAA formation is critical. Our lab has now established a model of exposing mice to e-cigarette vapor and observed that this is associated with increased risk for experimental AAA formation. In this resubmission, we propose to determine the role of inhaled nicotine in e-cigarette vapor on vascular inflammation and accelerated AAA formation, focusing on a signaling pathway whereby nicotine induces vascular oxidative stress leading to enhanced inflammatory gene activity, most notably Chi3l1. Different e-cigarette vapor exposure times will be used to delineate the intracellular signaling that leads to enhanced Chi3l1 expression, vascular inflammation and AAA formation. In addition, we will leverage our experience with cell culture models to elucidate the pro-inflammatory effects of nicotine, focusing on the miR-24-Chi3l1 pathway.