Chronic Inhaled Nicotine‐Induced Pulmonary Hypertension and Right Ventricular Remodeling are Mediated by Angiotensin‐II Type 1 Receptor

Abstract

Introduction Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary impacts of these nicotine-containing devices. Our group previously demonstrated that chronic inhaled nicotine induces pulmonary hypertension and right ventricular (RV) remodeling in mice, characterized by increased RV systolic pressure (RVSP) and RV free wall thickness during diastole (RVFWT;d). These changes were associated with upregulated RV angiotensin converting enzyme (ACE), leading us to hypothesize that these nicotine-induced effects are mediated by the renin-angiotensin system. ACE inhibitor and angiotensin-II receptor blocker use in a large retrospective pulmonary hypertension patient cohort was associated with improved survival. Here, we utilized losartan, a specific antagonist of the angiotensin-II type 1 receptor (AT1R), to further explore nicotine's cardiopulmonary effects. Methods: Male C57BL/6 mice received either nicotine vapor or room air for 12 hours per day, and exposure was measured by serum cotinine (559±57 ng/mL; comparable to human cigarette smokers or electronic cigarette users). A subset of mice was treated with losartan via osmotic mini-pump for 8 weeks. Losartan dosage was approximately 5.0 to 6.5 mg/kg/day due to body weight differences throughout the experiment. Cardiac structure and function were assessed using echocardiography and RV catheterization. Results: Chronic inhaled nicotine significantly increased RVSP (40.7±3.5 mmHg, n=11) versus air exposure (25.6±1.0 mmHg, n=11, p<0.005). Mice receiving both losartan and nicotine had significantly reduced RVSP (24.0±1.3 mmHg, n=12, p<0.005) versus nicotine alone. There was no difference in RVSP between air mice and either losartan-infused group (air-losartan: 23.7±1.2 mmHg, n=14). RVFWT;d was increased in nicotine mice (0.44±0.01 mm, n=12) versus air mice (0.31±0.01 mm, n=10, p<0.0001). Losartan infusion of nicotine mice resulted in significantly decreased RVFWT;d (0.34±0.01 mm, n=8, p<0.0001) versus nicotine alone. There was no difference in RVFWT;d between air mice and either losartan-infused group (air-losartan: 0.32±0.01 mm, n=7). Chronic inhaled nicotine increased RV internal diameter during diastole (RVID;d; 1.56±0.04 mm, n=12) versus air mice (1.24±0.07 mm, n=10, p<0.0001), suggesting RV dilation. RVID;d between air-exposed mice receiving losartan (1.23±0.04, n=7) and nicotine-exposed mice receiving losartan (1.44±0.03, n=8) was not significantly different. Neither nicotine nor losartan exposure resulted in changes to left ventricular structure and function. Conclusion: These findings provide the first preclinical evidence that AT1R antagonism can ameliorate chronic inhaled nicotine-induced pulmonary hypertension and RV remodeling.