Yue Wang1, Yue Wang1, Hong-Feng Jiang2, Hai-Ming Dang3, Meng-Ru Liu1, Xin-Yan Liu1, Yang Yu3, Jiang Xie4, Xiao-Jun Zhan5, Hui-Na Zhang6, Xiao-Fan Wu7. 1. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. 2. Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. 3. Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. 4. Department of Respiratory and Critical Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. 5. Sleep Medicine Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. 6. Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. 7. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China. drwuxf@163.com.
Abstract
PURPOSE: It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates β3 adrenergic receptor (β3 AR). However, the effect of selective β3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown. METHODS: We generated a CIH-induced atherosclerosis model through exposing ApoE-/- mice to CIH (8 h per day, cyclic inspiratory oxygen fraction 5-21%, 60-s cycle) for 6 weeks after 4-week high-fat dieting and investigated the effects of mirabegron, a selective β3 AR agonist, on CIH-induced atherosclerosis. The coronary endarterectomy (CE) specimens from coronary artery disease patients with OSA and without OSA were collected. RESULTS: The expression of β3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE-/- mice in CIH but not in normoxia. Mechanistically, mirabegron activated β3 AR and ameliorated intraplaque oxidative stress by suppressing p22phox expression and reactive oxygen species (ROS) level. In addition, in human CE specimens, β3 AR was also upregulated associated with increased p22phox expression and ROS level both in the lumen and in the plaque of coronary artery in OSA subjects. CONCLUSION: This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via β3 AR-mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.
PURPOSE: It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates β3 adrenergic receptor (β3 AR). However, the effect of selective β3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown. METHODS: We generated a CIH-induced atherosclerosis model through exposing ApoE-/- mice to CIH (8 h per day, cyclic inspiratory oxygen fraction 5-21%, 60-s cycle) for 6 weeks after 4-week high-fat dieting and investigated the effects of mirabegron, a selective β3 AR agonist, on CIH-induced atherosclerosis. The coronary endarterectomy (CE) specimens from coronary artery disease patients with OSA and without OSA were collected. RESULTS: The expression of β3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE-/- mice in CIH but not in normoxia. Mechanistically, mirabegron activated β3 AR and ameliorated intraplaque oxidative stress by suppressing p22phox expression and reactive oxygen species (ROS) level. In addition, in human CE specimens, β3 AR was also upregulated associated with increased p22phox expression and ROS level both in the lumen and in the plaque of coronary artery in OSA subjects. CONCLUSION: This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via β3 AR-mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.
Authors: Jimmy F P Berbée; Mariëtte R Boon; P Padmini S J Khedoe; Alexander Bartelt; Christian Schlein; Anna Worthmann; Sander Kooijman; Geerte Hoeke; Isabel M Mol; Clara John; Caroline Jung; Nadia Vazirpanah; Linda P J Brouwers; Philip L S M Gordts; Jeffrey D Esko; Pieter S Hiemstra; Louis M Havekes; Ludger Scheja; Joerg Heeren; Patrick C N Rensen Journal: Nat Commun Date: 2015-03-10 Impact factor: 14.919