Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice
Background Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored. Methods and Results We used human/m...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.033881 |
| _version_ | 1797205473127038976 |
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| author | C. Alicia Traughber Kara Timinski Ashutosh Prince Nilam Bhandari Kalash Neupane Mariam R. Khan Esther Opoku Emmanuel Opoku Gregory Brubaker Junchul Shin Junyoung Hong Babunageswararao Kanuri Elif G. Ertugral Prabhakara R. Nagareddy Chandrasekhar R. Kothapalli Olga Cherepanova Jonathan D. Smith Kailash Gulshan |
| author_facet | C. Alicia Traughber Kara Timinski Ashutosh Prince Nilam Bhandari Kalash Neupane Mariam R. Khan Esther Opoku Emmanuel Opoku Gregory Brubaker Junchul Shin Junyoung Hong Babunageswararao Kanuri Elif G. Ertugral Prabhakara R. Nagareddy Chandrasekhar R. Kothapalli Olga Cherepanova Jonathan D. Smith Kailash Gulshan |
| author_sort | C. Alicia Traughber |
| collection | DOAJ |
| description | Background Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored. Methods and Results We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram‐fed hyperlipidemic apolipoprotein E−/− mice showed significantly reduced interleukin‐1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram‐fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram‐treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell‐surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram‐treated macrophages, showing increased order‐state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram‐fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species. Conclusions Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD‐dependent as well as GsdmD‐independent manner. |
| first_indexed | 2024-04-24T08:51:41Z |
| format | Article |
| id | doaj.art-15b7d8b60152495897f66b350118e328 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-24T08:51:41Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-15b7d8b60152495897f66b350118e3282024-04-16T09:33:08ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802024-04-0113810.1161/JAHA.123.033881Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic MiceC. Alicia Traughber0Kara Timinski1Ashutosh Prince2Nilam Bhandari3Kalash Neupane4Mariam R. Khan5Esther Opoku6Emmanuel Opoku7Gregory Brubaker8Junchul Shin9Junyoung Hong10Babunageswararao Kanuri11Elif G. Ertugral12Prabhakara R. Nagareddy13Chandrasekhar R. Kothapalli14Olga Cherepanova15Jonathan D. Smith16Kailash Gulshan17Center for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USACenter for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USACenter for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USACenter for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USACenter for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USACenter for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USADepartment of Biology, Geology, and Environmental Sciences Cleveland State University Cleveland OH USADepartment of Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic Cleveland OH USADepartment of Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic Cleveland OH USADepartment of Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic Cleveland OH USADepartment of Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic Cleveland OH USADepartment of Internal Medicine, Cardiovascular Section University of Oklahoma Health Sciences Center (OUHSC) Oklahoma City OK USADepartment of Chemical & Biomedical Engineering Cleveland State University Cleveland OH USADepartment of Internal Medicine, Cardiovascular Section University of Oklahoma Health Sciences Center (OUHSC) Oklahoma City OK USADepartment of Chemical & Biomedical Engineering Cleveland State University Cleveland OH USADepartment of Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic Cleveland OH USADepartment of Cardiovascular and Metabolic Sciences Lerner Research Institute, Cleveland Clinic Cleveland OH USACenter for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USABackground Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored. Methods and Results We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram‐fed hyperlipidemic apolipoprotein E−/− mice showed significantly reduced interleukin‐1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram‐fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram‐treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell‐surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram‐treated macrophages, showing increased order‐state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram‐fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species. Conclusions Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD‐dependent as well as GsdmD‐independent manner.https://www.ahajournals.org/doi/10.1161/JAHA.123.033881atherosclerosisautophagydisulfiramefferocytosisgut microbiota |
| spellingShingle | C. Alicia Traughber Kara Timinski Ashutosh Prince Nilam Bhandari Kalash Neupane Mariam R. Khan Esther Opoku Emmanuel Opoku Gregory Brubaker Junchul Shin Junyoung Hong Babunageswararao Kanuri Elif G. Ertugral Prabhakara R. Nagareddy Chandrasekhar R. Kothapalli Olga Cherepanova Jonathan D. Smith Kailash Gulshan Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atherosclerosis autophagy disulfiram efferocytosis gut microbiota |
| title | Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice |
| title_full | Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice |
| title_fullStr | Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice |
| title_full_unstemmed | Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice |
| title_short | Disulfiram Reduces Atherosclerosis and Enhances Efferocytosis, Autophagy, and Atheroprotective Gut Microbiota in Hyperlipidemic Mice |
| title_sort | disulfiram reduces atherosclerosis and enhances efferocytosis autophagy and atheroprotective gut microbiota in hyperlipidemic mice |
| topic | atherosclerosis autophagy disulfiram efferocytosis gut microbiota |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.033881 |
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