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.
Highlights
Atherosclerosis is a chronic inflammatory response to injury of the arterial wall [1, 2]
Vascular inflammation stimulates the expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, in endothelial cells (ECs). ese effectors encourage monocyte adhesion and infiltration into the neointima lesion, followed by atheroma formation and subendothelial accumulation of lipid-laden macrophage foam cells [1, 3]
Foam cell formation is characterized by intracytoplasmic accumulation of cholesterol ester and depends on the balance among the uptake of oxidized low-density lipoprotein via CD36, International Journal of Endocrinology cholesterol esterification by acyl-CoA:cholesterol acyltransferase-1 (ACAT-1), and the efflux of free cholesterol controlled by the ATP-binding cassette transporter A1 (ABCA1) [2, 3]
Summary
Atherosclerosis is a chronic inflammatory response to injury of the arterial wall [1, 2]. Β-Endorphin is mainly produced and secreted in the pituitary gland [13] Both β-endorphin and μ-opioid receptors are expressed in synovial tissue, ECs, monocytes, macrophages, lymphocytes, and granulocytes [14,15,16,17,18]. Is peptide increases endothelin-1 release and decreases nitric oxide release from human ECs and monocytes via μ1-opioid receptors, which may lead to endothelial dysfunction [15]. We aimed at clarifying the effects of β-endorphin in vitro on the inflammatory response and adhesion of human THP-1 monocytes to human umbilical vein ECs (HUVECs). We assessed the inflammatory phenotype and foam cell formation in THP-1 monocytederived macrophages, as well as migration and proliferation of human aortic smooth muscle cells (HASMCs). Our in vivo studies focused on the development of atherosclerotic lesions in Apoe−/− mice
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