Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice
Abstract The regression, or resolution, of inflammation in atherosclerotic plaques is impaired in diabetes. However, the factors mediating this effect remain incomplete. We identified protein arginine methyltransferase 2 (PRMT2) as a protein whose expression in macrophages is reduced in hyperglycemi...
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| Format: | Article |
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Nature Portfolio
2022-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-15349-6 |
| _version_ | 1818510758401540096 |
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| author | Beyza Vurusaner Prashanth Thevkar-Nages Ravneet Kaur Chiara Giannarelli Michael J. Garabedian Edward A. Fisher |
| author_facet | Beyza Vurusaner Prashanth Thevkar-Nages Ravneet Kaur Chiara Giannarelli Michael J. Garabedian Edward A. Fisher |
| author_sort | Beyza Vurusaner |
| collection | DOAJ |
| description | Abstract The regression, or resolution, of inflammation in atherosclerotic plaques is impaired in diabetes. However, the factors mediating this effect remain incomplete. We identified protein arginine methyltransferase 2 (PRMT2) as a protein whose expression in macrophages is reduced in hyperglycemia and diabetes. PRMT2 catalyzes arginine methylation to target proteins to modulate gene expression. Because PRMT2 expression is reduced in cells in hyperglycemia, we wanted to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We, therefore, examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. Remarkably, we found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2 −/−) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention, as well as increased apoptosis and necrosis. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells. Consistently, Prmt2 −/− bone marrow-derived macrophages (BMDMs) showed an increased response of proinflammatory genes to LPS and a decreased response of inflammation resolving genes to IL-4. This increased response to LPS in Prmt2 −/− BMDMs occurs via enhanced NF-kappa B activity. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression via a heightened inflammatory response in macrophages. That PRMT2 expression was lower in myeloid cells in plaques from human subjects with diabetes supports the relevance of our findings to human atherosclerosis. |
| first_indexed | 2024-12-10T23:24:24Z |
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| id | doaj.art-cf0ea2a5008f41f69be02fcbfb201139 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-10T23:24:24Z |
| publishDate | 2022-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cf0ea2a5008f41f69be02fcbfb2011392022-12-22T01:29:38ZengNature PortfolioScientific Reports2045-23222022-07-0112111210.1038/s41598-022-15349-6Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic miceBeyza Vurusaner0Prashanth Thevkar-Nages1Ravneet Kaur2Chiara Giannarelli3Michael J. Garabedian4Edward A. Fisher5Division of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University Grossman School of MedicineDivision of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University Grossman School of MedicineDivision of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University Grossman School of MedicineDivision of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University Grossman School of MedicineDepartment of Microbiology, New York University Grossman School of MedicineDivision of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University Grossman School of MedicineAbstract The regression, or resolution, of inflammation in atherosclerotic plaques is impaired in diabetes. However, the factors mediating this effect remain incomplete. We identified protein arginine methyltransferase 2 (PRMT2) as a protein whose expression in macrophages is reduced in hyperglycemia and diabetes. PRMT2 catalyzes arginine methylation to target proteins to modulate gene expression. Because PRMT2 expression is reduced in cells in hyperglycemia, we wanted to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We, therefore, examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. Remarkably, we found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2 −/−) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention, as well as increased apoptosis and necrosis. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells. Consistently, Prmt2 −/− bone marrow-derived macrophages (BMDMs) showed an increased response of proinflammatory genes to LPS and a decreased response of inflammation resolving genes to IL-4. This increased response to LPS in Prmt2 −/− BMDMs occurs via enhanced NF-kappa B activity. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression via a heightened inflammatory response in macrophages. That PRMT2 expression was lower in myeloid cells in plaques from human subjects with diabetes supports the relevance of our findings to human atherosclerosis.https://doi.org/10.1038/s41598-022-15349-6 |
| spellingShingle | Beyza Vurusaner Prashanth Thevkar-Nages Ravneet Kaur Chiara Giannarelli Michael J. Garabedian Edward A. Fisher Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice Scientific Reports |
| title | Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice |
| title_full | Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice |
| title_fullStr | Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice |
| title_full_unstemmed | Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice |
| title_short | Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice |
| title_sort | loss of prmt2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice |
| url | https://doi.org/10.1038/s41598-022-15349-6 |
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