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Mirabegron Ameliorated Atherosclerosis of ApoE−/− Mice in Chronic Intermittent Hypoxia but Not in Normoxia

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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.

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Availability of Data and Material

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Beijing Natural Science Foundation and Municipal Education Commission Grant KZ202010025045; Beijing Talents Project 2020A39; the National Natural Science Foundation of China (NSFC) Grants 81670317, 82071573, and 81470492, and Capitals’ s Funds for Health Improvement and Research of China 2018-2-2064 to Xiao-fan Wu.

Author information

Authors and Affiliations

  1. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Yue Wang, Yue Wang, Meng-ru Liu, Xin-yan Liu & Xiao-fan Wu

  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

    Hong-feng Jiang

  3. Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Hai-ming Dang & Yang Yu

  4. Department of Respiratory and Critical Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Jiang Xie

  5. Sleep Medicine Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Xiao-jun Zhan

  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

    Hui-na Zhang

Authors
  1. Yue Wang
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  2. Yue Wang
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Contributions

Yue Wang (the first author) and Yue Wang (the second author) performed experiments, analyzed and interpreted the data, and drafted the manuscript; Hong-feng Jiang, Meng-ru Liu, Xin-yan Liu and Jiang Xie conducted the experiments; Hai-ming Dang and Yang Yu performed coronary endarterectomy. Xiao-jun Zhan and Hui-na Zhang provided reagents, analyzed and interpreted the data and edited the paper. Xiao-fan Wu contributed resources and secured funding, designed research, supervised the project and reviewed the manuscript. Yue Wang (the first author) is a doctorial candidate of grade 2020; Yue Wang (the second author) is a doctorial candidate of grade 2019. The two authors contributed equally to this work.

Corresponding author

Correspondence to Xiao-fan Wu.

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Ethics Approval

All procedures involving human participants were authorized by the Medical Ethics Committee of Beijing Anzhen Hospital and adhered to the Declaration of Helsinki and its later amendments or comparable ethical standards. All procedures involving animals were approved by the Capital Medical University Animal Experimentation Ethics Committee and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Written informed consent was obtained from all subjects enrolled in this study.

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Wang, Y., Wang, Y., Jiang, Hf. et al. Mirabegron Ameliorated Atherosclerosis of ApoE−/− Mice in Chronic Intermittent Hypoxia but Not in Normoxia. Cardiovasc Drugs Ther 36, 805–815 (2022). https://doi.org/10.1007/s10557-021-07196-w

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