Angiotensin II type 1 receptor mediates pulmonary hypertension and right ventricular remodeling induced by inhaled nicotine

Abstract

Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary health impacts of these nicotine-containing devices. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in mice. These changes were associated with upregulated RV angiotensin-converting enzyme (ACE). Angiotensin-II receptor blockers (ARBs) have been shown to reverse cigarette smoking-induced PH in rats. ACE inhibitor and ARB use in a large retrospective PH patient cohort is associated with improved survival. Here, we utilized losartan (an ARB specific for angiotensin-II type 1 receptor) to further explore nicotine-induced PH. Male C57BL/6 mice received nicotine vapor for 12 hours per day, and exposure was assessed using serum cotinine to achieve levels comparable to human smokers or electronic cigarette users. Mice were exposed to nicotine for 8 weeks and a subset was treated with losartan via osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin-II in the RV and lung, this finding was non-significant. Chronic, inhaled nicotine significantly increased RV systolic pressure and RV free wall thickness versus air control. These parameters were significantly lower in mice receiving both nicotine and losartan. Nicotine significantly increased RV internal diameter, with no differences seen between the nicotine and nicotine-losartan group. Neither nicotine nor losartan effect left ventricular structure or function. These findings provide the first evidence that antagonism of the angiotensin-II type 1 receptor can ameliorate chronic, inhaled nicotine-induced PH and RV remodeling.

The efficacy and safety of Sacubitril/Valsartan on pulmonary hypertension in hemodialysis patients

“…Previous studies had shown that angiotensin II type 1 receptor blockers reduced pulmonary vascular remodeling. Fried et al had confirmed that losartan was related to ameliorate chronic, inhaled nicotine-induced PH and right ventricular remodeling ( 26 ). Lu et al found that valsartan slowed down the development of experimental PH in mice ( 27 ).…”

Nicotine and novel tobacco products drive adverse cardiac remodeling and dysfunction in preclinical studies

“…Nicotine vapor was produced by bubbling air through a gas-washing bottle containing free base nicotine (Sigma-Aldrich, St. Louis, MO), as previously described ( 32 , 33 ). The concentrated nicotine vapor was then diluted with air and evenly distributed to each chamber at a flow rate of 7 to 8 L/min.…”

“…We have previously shown that chronic, inhaled nicotine exposure causes pulmonary hypertension associated with RV remodeling, elevated RV brain-type natriuretic peptide, and increased expression of angiotensin-converting enzyme in the RV, but not LV ( 32 ). These changes are abrogated by treatment with losartan, a specific AT 1 R antagonist ( 33 ). Nicotine-induced pulmonary hypertension, RV remodeling, and vascular dysfunction are ameliorated by α7 nicotinic cholinergic receptor knockout, and are absent in female mice ( 58 ).…”

Harmful Impact of Tobacco Smoking and Alcohol Consumption on the Atrial Myocardium

“…Exposure to tobacco smoke induced cardiac remodeling via oxidative stress in rats in several studies [ 54 , 55 ]. A variety of antioxidants and antagonists of the RAAS were demonstrated to attenuate this [ 46 , 47 , 56 , 57 , 58 , 59 , 60 ]. An increase of glucose metabolism was found in the early phase of cardiac remodeling after tobacco smoke exposure, with an increase in glycolytic pathways [ 58 ] and insulin resistance [ 61 ].…”