β-Endorphin Mediates the Development and Instability of Atherosclerotic Plaques

Taisuke Okano; Kengo Sato; Remina Shirai; Tomomi Seki; Koichiro Shibata; Tomoyuki Yamashita; Ayaka Koide; Hitomi Tezuka; Yusaku Mori; Tsutomu Hirano; Takuya Watanabe

doi:10.1155/2020/4139093

β-Endorphin Mediates the Development and Instability of Atherosclerotic Plaques

Int J Endocrinol. 2020 Mar 28:2020:4139093. doi: 10.1155/2020/4139093. eCollection 2020.

Authors

Affiliations

¹ Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
² Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
³ Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
⁴ Department of Internal Medicine, Ushioda General Hospital/Clinic, Yokohama, Japan.

Abstract

β-Endorphin, an endogenous opioid peptide, and its μ-opioid receptor are expressed in brain, liver, and peripheral tissues. β-Endorphin induces endothelial dysfunction and is related to insulin resistance. We clarified the effects of β-endorphin on atherosclerosis. We assessed the effects of β-endorphin on the inflammatory response and monocyte adhesion in human umbilical vein endothelial cells (HUVECs), foam cell formation, and the inflammatory phenotype in THP-1 monocyte-derived macrophages, and migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro. We also assessed the effects of β-endorphin on aortic lesions in Apoe ^-/- mice in vivo. The μ-opioid receptor (OPRM1) was expressed in THP-1 monocytes, macrophages, HASMCs, HUVECs, and human aortic endothelial cells. β-Endorphin significantly increased THP-1 monocyte adhesion to HUVECs and induced upregulation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin via nuclear factor-κB (NF-κB) and p38 phosphorylation in HUVECs. β-Endorphin significantly increased HUVEC proliferation and enhanced oxidized low-density lipoprotein-induced foam cell formation in macrophages. β-Endorphin also significantly shifted the macrophage phenotype to proinflammatory M1 rather than anti-inflammatory M2 via NF-κB phosphorylation during monocyte-macrophage differentiation and increased migration and apoptosis in association with c-jun-N-terminal kinase, p38, and NF-κB phosphorylation in HASMCs. Chronic β-endorphin infusion into Apoe ^-/- mice significantly aggravated the development of aortic atherosclerotic lesions, with an increase in vascular inflammation and the intraplaque macrophage/smooth muscle cell ratio, an index of plaque instability. Our study provides the first evidence that β-endorphin contributes to the acceleration of the progression and instability of atheromatous plaques. Thus, μ-opioid receptor antagonists may be useful for the prevention and treatment of atherosclerosis.