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Nicotine and Epigenetic Transgenerational Risk of Abdominal Aortic Aneurysm

Institution: Palo Alto Veterans Institute For Research
Investigator(s): Joshua Spin, M.D.-Ph.D.
Award Cycle: 2017 (Cycle 26) Grant #: 26IP-0041 Award: $326,640
Subject Area: Cardiovascular Disease
Award Type: High Impact Pilot Award

Initial Award Abstract

Cigarette smoking not only increases an individual’s risk for developing abdominal aortic aneurysm (AAA: an abnormal enlargement of the aorta, the body's main artery), but may also cause biological changes that increase the likelihood of that individual’s offspring developing an aneurysm. This is also apparently true for exposure to nicotine. We intend to investigate how this occurs, and to what extent. Smoking is one of the most important risk factors for the development of AAA, which is a significant source of mortality and morbidity in the U.S. AAA rupture may occur in 15,000 patients annually or more, with fewer than half surviving to treatment. Over 90% of individuals diagnosed with AAA are either current or prior tobacco users. In addition, several small studies have associated continued cigarette smoking with accelerated aneurysm expansion. Nicotine is one of the most crucial chemical constituents of tobacco smoke, and we have found that it is capable of augmenting aneurysm formation in animal models of AAA. Expression of an individual’s genes depends not only on the sequence of their DNA, but also on other control mechanisms. These include special chemical modifications like methylation of regions of DNA that can silence or activate genes, or changes in small noncoding RNAs (called microRNAs) that can suppress gene expression. It has been recently appreciated that exposure to environmental toxins like smoke and nicotine can alter these “epigenetic” marks, potentially increasing disease risk in the next generation and even beyond, and that exposure to nicotine in the womb can permanently increase such risk. Studies in humans and animals have shown that smoking can alter microRNA expression in sperm, and that parental exposure to nicotine may change their children’s and even grandchildren’s susceptibility to asthma, high blood pressure, and diabetes. Our preliminary data suggest that maternal exposure to nicotine in mice can increase the risk of their progeny developing AAA. Using implanted pumps, we will expose either male or female mice to nicotine levels consistent with moderate-to-heavy smoking in humans. This treatment will take place either prior to mating, or during mating. We will measure changes in epigenetic marks in the blood and tissues, and employ a mouse model of AAA to examine their progeny’s susceptibility to aneurysm. We will also measure whether the progeny have changes in vessel stiffness or blood pressure response. Tissues and blood from the offspring will be examined for changes in inflammatory factors, growth factors, and other pro-aneurysmal stimuli. We will also study the DNA of the offspring, looking for epigenetic changes, and perform cell culture experiments to examine the mechanisms involved.