Sex Differences in Atherosclerosis in ApoE ‐/‐ Mice exposed to Nicotine and Cigarette Smoke

Abstract

Smoking is the foremost modifiable risk factor for cardiovascular disease, the leading cause of death in the U.S., yet almost 14% of American adults continue to smoke. Cigarettes contain nicotine, a highly addictive stimulant which prevents users from quitting smoking without withdrawal. Nicotine and other chemicals in cigarette smoke damage the endothelium, a process that in turn influences smooth muscle cells and contributes to atherosclerosis or plaque build-up in the arteries causing cardiovascular diseases. Gender differences have emerged between risk for both cardiovascular disease and the effect of smoking on cardiovascular disease. While risk of developing cardiovascular disease is highest in men, women's risk increases post-menopause, which may be partly explained by a decrease in protective estrogen levels. In addition, while slightly more men smoke than women (15% vs 13%), smoking is more harmful to women's cardiovascular system, resulting in an increased risk for heart attacks compared to men with a similar background. Despite understanding the role of smoking on the cardiovascular system and apparent human sex differences the specific processes accounting for female and male differences and whether nicotine alone is sufficient for these mechanisms is not fully understood. Therefore, we exposed female and male ApoE-/- (8 mice per group) to either nicotine in drinking water (0.2 mg/ml) or cigarette smoke for 4 months. Exposure was matched to a comparable nicotine ingestion by a moderate smoker. Males exposed to nicotine or smoke accrued significantly more plaque in the aortic arch (22.4 ± 7.2 and 21.7 ± 5%, respectively), but not descending aorta, compared to controls (12.4 ± 4.7%). In contrast, females exposed to nicotine and cigarette smoke accumulated significantly more plaque in the arch (30.3 ± 8.5% and 38.8 ± 4.3%, respectively) and descending aorta (3.4 ± 0.9% and 5.8 ± 2.7%, respectively), compared with controls (arch: 18.7 ± 5% and descending aorta: 1.5 ± 0.5%). These sex differences were independent of changes in cholesterol, triglycerides and LDL, but correlated with changes in the blood levels of IL-17. Altogether these data suggest that females are at higher risk of developing atherosclerosis than males exposed to nicotine and cigarette smoke which could be mediated by an inflammatory response induced by IL-17.