The Role of Sex in the Effects of Smoking and Nicotine in Cardiovascular Function, Atherosclerosis, and Inflammation

Abstract

Cigarette smoke (CS) invokes an inflammatory response involving increased levels of circulating cytokines and chemokines, vascular dysfunction, and atherosclerosis. The role of sex and nicotine in CS effects in cardiovascular function and atherosclerosis is unexplored. To assess the role of sex, male and female C57Bl/6 WT (wild type) and ApoE-/- mice were exposed to CS and nicotine for 16 weeks to bridge this literature gap. Heart rate and endothelial function were measured in the aorta of WT mice, while plasma levels of lipids, cytokines and chemokines and aortic plaque burden was assessed in ApoE-/- mice. CS increased heart rate to similar levels in both sexes and induced a stronger impairment in endothelial function in males and more plaque in females than nicotine. Females showed a higher necrotic core area at basal compared with males, while males had a higher calcification area than females by CS. Senescence-associated GLB1/?-galactosidase (SA-GLB1) activity was elevated similarly in both sexes by both treatments. Total cholesterol (TC) was elevated by CS in both sexes. CS increased triglycerides (TG), very-low density lipoprotein (VLDL) and high-density lipoprotein (HDL) only in males and low-density lipoprotein (LDL) only in females. Interleukin 17A (IL17A) was upregulated by CS and nicotine in both sexes, while CS upregulated C-X-C motif chemokine ligand 5 (CXCL5/LIX) and interleukin 1 alpha (IL1A) in males and females, respectively. Additionally, nicotine metabolism showed sex specific responses to nicotine, but not smoking. Overall, we identified sex-specific pro-atherogenic responses to CS in the lipid profile, plaque area and composition and inflammatory markers. Males present a stronger impairment in endothelia dysfunction in WT mice, while females a stronger plaque burden in ApoE-/- mice exposed to CS. Elevated HDL and estrogens in males may offer partial protection against the harmful effects of CS. In contrast, elevated LDL and a pro-inflammatory state may promote a stronger pro-atherogenic phenotype in females exposed to CS.