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Proc Natl Acad Sci U S A. 2019 May 28;116(22):10937-10942. doi: 10.1073/pnas.1901655116. Epub 2019 May 13.

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.

Author information

1
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 250012 Jinan, China.
2
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
3
Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, 200032 Shanghai, China.
4
Department of Clinical Laboratory, The Second Hospital of Shandong University, Shandong, 250012 Jinan, China.
5
Clinical Laboratory, The Affiliated Hospital of Qingdao University, 266003 Qingdao, China.
6
Department of Emergency, Qilu Hospital of Shandong University, Shandong, 250012 Jinan, China.
7
Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, China.
8
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, 266071 Qingdao, China.
9
Central Research Laboratory, The Affiliated Hospital of Qingdao University, 266071 Qingdao, China.
10
Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Shenzhen University, 518060 Shenzhen, People's Republic of China.
11
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 250012 Jinan, China; yihai.cao@ki.se zhangyun@sdu.edu.cn.
12
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; yihai.cao@ki.se zhangyun@sdu.edu.cn.

Abstract

Mirabegron (Myrbetriq) is a β3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the β3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E-/- (ApoE -/-) and low-density lipoprotein (LDL) receptor-/- (Ldlr -/-) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis.

KEYWORDS:

adipose tissue; atherosclerosis; lipolysis; mirabegron; plaque instability

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