Cardiopulmonary protection against nicotine‐induced pulmonary hypertension and right ventricular remodeling in mice is not mediated by ovarian hormones

Abstract

IntroductionElectronic cigarette use has increased globally prompting a joint committee of international cardiovascular research organizations to call for improved understanding of the health effects of nicotine. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in male but not female mice, suggesting sex differences in nicotine‐related pathology. Clinically, biological females develop PH more often, but have less severe disease than biological males, likely due to the cardiopulmonary protective effects of estrogen. Nicotine is also metabolized more rapidly in biological females due to sex hormone‐mediated differences in cytochrome P450 activity. These findings led us to hypothesize that female mice are protected against nicotine‐induced PH by a sex hormone‐dependent mechanism. Here, we assessed the role of ovarian hormones in a murine model of nicotine‐induced PH.MethodsFemale C57BL/6J mice were ovariectomized (OVX) one week prior to nicotine exposure. Intact and OVX mice were exposed to nicotine vapor or room air for 12 hours per day for 8 weeks. Nicotine exposure was measured using serum cotinine, which was comparable to human electronic cigarette users, and was not significantly different between intact (421 ± 101 ng/mL) and OVX (314 ± 61 ng/mL) mice. Cardiac structure and function were assessed using echocardiography and RV catheterization.ResultsIn contrast to previous findings in male mice, inhaled nicotine does not cause PH (measured by RV systolic pressure, RVSP) in intact female mice (24.0 ± 0.5 mmHg, n=7 in air vs. 22.7 ± 0.4 mmHg, n=9 in nicotine). RVSP was also unaffected by OVX (24.4 ± 0.9 mmHg, n=9 in air vs. 23.6 ± 0.6 mmHg, n=10 in nicotine). RV free wall thickness during diastole (RV FWT;d) was not significantly different between air‐exposed intact mice (0.328 ± 0.023 mm, n=8), nicotine‐exposed intact mice (0.292 ± 0.015 mm, n=10), air‐exposed OVX mice (0.315 ± 0.021 mm, n=8), and nicotine‐exposed OVX mice (0.293 ± 0.013 mm, n=10). RV internal diameter during diastole (RVID;d) was, likewise, not significantly different between air‐exposed intact mice (1.30 ± 0.03 mm, n=8), nicotine‐exposed intact mice (1.34 ± 0.04 mm, n=10), air‐exposed OVX mice (1.23 ± 0.05 mm, n=8), and nicotine‐exposed OVX mice (1.24 ± 0.05 mm, n=10).ConclusionIn this study, we found no differences in serum cotinine, RVSP, RV FWT;d, or RVID;d between intact and OVX females, leading us to conclude that ovarian hormones do not mediate cardiopulmonary protection against nicotine‐induced PH. Due to profound sex differences in clinical PH pathogenesis and nicotine metabolism, further studies (including exploration of androgen‐driven RV remodeling) are necessary to illuminate mechanisms underlying protection from nicotine‐induced pathology in female mice.