<i>β</i>-Endorphin Mediates the Development and Instability of Atherosclerotic Plaques

Abstract

<i>β</i>-Endorphin, an endogenous opioid peptide, and its <i>μ</i>-opioid receptor are expressed in brain, liver, and peripheral tissues. <i>β</i>-Endorphin induces endothelial dysfunction and is related to insulin resistance. We clarified the effects of <i>β</i>-endorphin on atherosclerosis. We assessed the effects of <i>β</i>-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 <i>β</i>-endorphin on aortic lesions in <i>Apoe</i> ^-/- mice in vivo. The <i>μ</i>-opioid receptor (OPRM1) was expressed in THP-1 monocytes, macrophages, HASMCs, HUVECs, and human aortic endothelial cells. <i>β</i>-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-<i>κ</i>B (NF-<i>κ</i>B) and p38 phosphorylation in HUVECs. <i>β</i>-Endorphin significantly increased HUVEC proliferation and enhanced oxidized low-density lipoprotein-induced foam cell formation in macrophages. <i>β</i>-Endorphin also significantly shifted the macrophage phenotype to proinflammatory M1 rather than anti-inflammatory M2 via NF-<i>κ</i>B phosphorylation during monocyte-macrophage differentiation and increased migration and apoptosis in association with c-jun-N-terminal kinase, p38, and NF-<i>κ</i>B phosphorylation in HASMCs. Chronic <i>β</i>-endorphin infusion into <i>Apoe</i> ^-/- 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 <i>β</i>-endorphin contributes to the acceleration of the progression and instability of atheromatous plaques. Thus, <i>μ</i>-opioid receptor antagonists may be useful for the prevention and treatment of atherosclerosis.