Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages
Nalmefene, an antagonist of mu- and delta-opioid receptors and a partial agonist of kappa-opioid receptors, has shown promise in reducing alcohol consumption among patients with alcohol dependence. Opioid receptors play pivotal roles in various physiological processes, including those related to per...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-07-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580824000529 |
| _version_ | 1797246810468646912 |
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| author | Mitsuhisa Koga Koshun Inada Ayano Yamada Kana Maruoka Atsushi Yamauchi |
| author_facet | Mitsuhisa Koga Koshun Inada Ayano Yamada Kana Maruoka Atsushi Yamauchi |
| author_sort | Mitsuhisa Koga |
| collection | DOAJ |
| description | Nalmefene, an antagonist of mu- and delta-opioid receptors and a partial agonist of kappa-opioid receptors, has shown promise in reducing alcohol consumption among patients with alcohol dependence. Opioid receptors play pivotal roles in various physiological processes, including those related to peripheral inflammatory diseases such as colitis and arthritis, as well as functions in the immune system and phagocytosis. Atherosclerosis, a chronic inflammatory disease, progresses through the phagocytosis and uptake of oxidized low-density lipoprotein (oxLDL) by macrophages in atherosclerotic plaques. Despite this knowledge, it remains unclear whether nalmefene influences the formation of atherosclerotic plaques and increases the risk of serious cardiovascular events. This study aims to elucidate the impact of nalmefene on atherosclerosis in apolipoprotein E knockout (ApoE KO) mice and peritoneal macrophages in vitro.In this experiment, 8-week-old male ApoE KO mice were fed a high-fat diet intraperitoneally administered either vehicle (saline) or nalmefene (1 mg and 3 mg kg−1 day−1) for 21 days. Oil red O-staining and immunohistochemistry with an anti-MOMA2 (monocyte/macrophage) antibody showed that a dose-dependent increase in atherosclerotic plaque formation and augmentation of macrophage-rich plaque formation in ApoE-KO mice. Further investigations focused on the effects of nalmefene on the expression of scavenger receptor CD36 in RAW264.7 cells, conducted through western blotting analysis. Nalmefene demonstrated a significant increase in CD36 protein expression in RAW264.7 cells. To explore the impact on oxidized LDL uptake in peritoneal macrophages, cells were treated with nalmefene (300 μg/mL) for 24 h, followed by the addition of DiI-labeled oxLDL (DiI-oxLDL) for 4 h. Nalmefene significantly enhanced DiI-oxLDL uptake in macrophages. Additionally, treatment with nalmefene (300 μg/mL) for 24 h decreased the mRNA expression of mu-, delta-, and kappa-opioid receptors in RAW264.7 cells.In conclusion, nalmefene may augment oxLDL uptake by macrophages through increased CD36 expression and decreased opioid receptor, thereby contributing to atherosclerotic plaque formation and vulnerability. Consequently, the use of nalmefene may be associated with an elevated risk of cardiovascular events. |
| first_indexed | 2024-04-24T19:48:43Z |
| format | Article |
| id | doaj.art-a8c287eb789b4a3a827c4054fb21d38b |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-04-24T19:48:43Z |
| publishDate | 2024-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-a8c287eb789b4a3a827c4054fb21d38b2024-03-25T04:17:53ZengElsevierBiochemistry and Biophysics Reports2405-58082024-07-0138101688Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophagesMitsuhisa Koga0Koshun Inada1Ayano Yamada2Kana Maruoka3Atsushi Yamauchi4Department of Drug Delivery, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan; Corresponding author.Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, JapanDepartment of Drug Delivery, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, JapanDepartment of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, JapanDepartment of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, JapanNalmefene, an antagonist of mu- and delta-opioid receptors and a partial agonist of kappa-opioid receptors, has shown promise in reducing alcohol consumption among patients with alcohol dependence. Opioid receptors play pivotal roles in various physiological processes, including those related to peripheral inflammatory diseases such as colitis and arthritis, as well as functions in the immune system and phagocytosis. Atherosclerosis, a chronic inflammatory disease, progresses through the phagocytosis and uptake of oxidized low-density lipoprotein (oxLDL) by macrophages in atherosclerotic plaques. Despite this knowledge, it remains unclear whether nalmefene influences the formation of atherosclerotic plaques and increases the risk of serious cardiovascular events. This study aims to elucidate the impact of nalmefene on atherosclerosis in apolipoprotein E knockout (ApoE KO) mice and peritoneal macrophages in vitro.In this experiment, 8-week-old male ApoE KO mice were fed a high-fat diet intraperitoneally administered either vehicle (saline) or nalmefene (1 mg and 3 mg kg−1 day−1) for 21 days. Oil red O-staining and immunohistochemistry with an anti-MOMA2 (monocyte/macrophage) antibody showed that a dose-dependent increase in atherosclerotic plaque formation and augmentation of macrophage-rich plaque formation in ApoE-KO mice. Further investigations focused on the effects of nalmefene on the expression of scavenger receptor CD36 in RAW264.7 cells, conducted through western blotting analysis. Nalmefene demonstrated a significant increase in CD36 protein expression in RAW264.7 cells. To explore the impact on oxidized LDL uptake in peritoneal macrophages, cells were treated with nalmefene (300 μg/mL) for 24 h, followed by the addition of DiI-labeled oxLDL (DiI-oxLDL) for 4 h. Nalmefene significantly enhanced DiI-oxLDL uptake in macrophages. Additionally, treatment with nalmefene (300 μg/mL) for 24 h decreased the mRNA expression of mu-, delta-, and kappa-opioid receptors in RAW264.7 cells.In conclusion, nalmefene may augment oxLDL uptake by macrophages through increased CD36 expression and decreased opioid receptor, thereby contributing to atherosclerotic plaque formation and vulnerability. Consequently, the use of nalmefene may be associated with an elevated risk of cardiovascular events.http://www.sciencedirect.com/science/article/pii/S2405580824000529NalmefeneAtherosclerosisSide effectOpioid receptors |
| spellingShingle | Mitsuhisa Koga Koshun Inada Ayano Yamada Kana Maruoka Atsushi Yamauchi Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages Biochemistry and Biophysics Reports Nalmefene Atherosclerosis Side effect Opioid receptors |
| title | Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages |
| title_full | Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages |
| title_fullStr | Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages |
| title_full_unstemmed | Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages |
| title_short | Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages |
| title_sort | nalmefene an opioid receptor modulator aggravates atherosclerotic plaque formation in apolipoprotein e knockout mice by enhancing oxidized low density lipoprotein uptake in macrophages |
| topic | Nalmefene Atherosclerosis Side effect Opioid receptors |
| url | http://www.sciencedirect.com/science/article/pii/S2405580824000529 |
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