Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice
Background: Hypertriglyceridemia (HTG) increases the risk for atherosclerotic cardiovascular disease, but underlying mechanisms are incompletely understood. Circulating monocytes play an important role in atherogenesis by infiltrating arterial walls, where they differentiate into macrophages. We tes...
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MDPI AG
2022-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/11/1795 |
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| author | Xueying Peng Zeqin Lian Xiao-Yuan Dai Perrard Yunjie Xiao Jing Ni Veronica O’Brien Henry Dong Henry J. Pownall Christie M. Ballantyne Huaizhu Wu |
| author_facet | Xueying Peng Zeqin Lian Xiao-Yuan Dai Perrard Yunjie Xiao Jing Ni Veronica O’Brien Henry Dong Henry J. Pownall Christie M. Ballantyne Huaizhu Wu |
| author_sort | Xueying Peng |
| collection | DOAJ |
| description | Background: Hypertriglyceridemia (HTG) increases the risk for atherosclerotic cardiovascular disease, but underlying mechanisms are incompletely understood. Circulating monocytes play an important role in atherogenesis by infiltrating arterial walls, where they differentiate into macrophages. We tested the hypothesis that HTG is mechanistically linked to atherogenesis by altering the monocyte phenotype and infiltration into atherosclerotic lesions in a model of diet-induced atherogenesis in Ldlr<sup>−/−</sup> mice. Methods: HTG was induced in male Ldlr<sup>−/−</sup> mice, fed a Western, high-fat high-cholesterol diet, by daily injection of poloxamer 407 (P407), a lipoprotein lipase inhibitor, for seven weeks. Atherosclerosis, monocyte phenotypes, and monocyte migration into atherosclerotic lesions were determined by well-validated methods. Results: Compared with the saline control, P407 injection in Ldlr<sup>−/−</sup> mice rapidly induced profound and persistent HTG, modestly elevated plasma cholesterol levels, and increased levels of triglyceride and cholesterol carried in very-low-density lipoprotein and low-density lipoprotein. Unexpectedly, mice receiving P407 versus saline control showed less atherosclerosis. Following induction of HTG by P407, CD36<sup>+</sup> (also CD11c<sup>+</sup>), but not CD36<sup>−</sup> (CD11c<sup>−</sup>), monocytes showed early increases in lipid accumulation, but the number of CD36<sup>+</sup> (not CD36<sup>−</sup>) monocytes was dramatically decreased afterwards in the circulation until the end of the test. Concurrently, CD36<sup>+</sup> (CD11c<sup>+</sup>) monocyte migration into atherosclerotic lesions was also reduced in mice receiving P407 versus controls. Conclusions: P407 induced severe HTG, but reduced atherosclerosis, in Ldlr<sup>−/−</sup> mice, possibly because of profound reductions of circulating CD36<sup>+</sup> (CD11c<sup>+</sup>) monocytes, leading to decreased monocyte migration into atherosclerotic lesions. |
| first_indexed | 2024-03-10T01:25:07Z |
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| id | doaj.art-bc08e2051f9a4c01b99a11cc5049aa32 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:25:07Z |
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| spelling | doaj.art-bc08e2051f9a4c01b99a11cc5049aa322023-11-23T13:52:53ZengMDPI AGCells2073-44092022-05-011111179510.3390/cells11111795Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> MiceXueying Peng0Zeqin Lian1Xiao-Yuan Dai Perrard2Yunjie Xiao3Jing Ni4Veronica O’Brien5Henry Dong6Henry J. Pownall7Christie M. Ballantyne8Huaizhu Wu9Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, ChinaDepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USADepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USADepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USADepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USADepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USADepartment of Pediatrics, Children’s Hospital of Pittsburgh UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USACenter for Bioenergetics, Houston Methodist Research Institute, Houston, TX 77030, USADepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USADepartment of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USABackground: Hypertriglyceridemia (HTG) increases the risk for atherosclerotic cardiovascular disease, but underlying mechanisms are incompletely understood. Circulating monocytes play an important role in atherogenesis by infiltrating arterial walls, where they differentiate into macrophages. We tested the hypothesis that HTG is mechanistically linked to atherogenesis by altering the monocyte phenotype and infiltration into atherosclerotic lesions in a model of diet-induced atherogenesis in Ldlr<sup>−/−</sup> mice. Methods: HTG was induced in male Ldlr<sup>−/−</sup> mice, fed a Western, high-fat high-cholesterol diet, by daily injection of poloxamer 407 (P407), a lipoprotein lipase inhibitor, for seven weeks. Atherosclerosis, monocyte phenotypes, and monocyte migration into atherosclerotic lesions were determined by well-validated methods. Results: Compared with the saline control, P407 injection in Ldlr<sup>−/−</sup> mice rapidly induced profound and persistent HTG, modestly elevated plasma cholesterol levels, and increased levels of triglyceride and cholesterol carried in very-low-density lipoprotein and low-density lipoprotein. Unexpectedly, mice receiving P407 versus saline control showed less atherosclerosis. Following induction of HTG by P407, CD36<sup>+</sup> (also CD11c<sup>+</sup>), but not CD36<sup>−</sup> (CD11c<sup>−</sup>), monocytes showed early increases in lipid accumulation, but the number of CD36<sup>+</sup> (not CD36<sup>−</sup>) monocytes was dramatically decreased afterwards in the circulation until the end of the test. Concurrently, CD36<sup>+</sup> (CD11c<sup>+</sup>) monocyte migration into atherosclerotic lesions was also reduced in mice receiving P407 versus controls. Conclusions: P407 induced severe HTG, but reduced atherosclerosis, in Ldlr<sup>−/−</sup> mice, possibly because of profound reductions of circulating CD36<sup>+</sup> (CD11c<sup>+</sup>) monocytes, leading to decreased monocyte migration into atherosclerotic lesions.https://www.mdpi.com/2073-4409/11/11/1795poloxamer 407atherogenesishypertriglyceridemiafoamy monocyteslipid metabolismmonocyte phenotype |
| spellingShingle | Xueying Peng Zeqin Lian Xiao-Yuan Dai Perrard Yunjie Xiao Jing Ni Veronica O’Brien Henry Dong Henry J. Pownall Christie M. Ballantyne Huaizhu Wu Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice Cells poloxamer 407 atherogenesis hypertriglyceridemia foamy monocytes lipid metabolism monocyte phenotype |
| title | Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice |
| title_full | Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice |
| title_fullStr | Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice |
| title_full_unstemmed | Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice |
| title_short | Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr<sup>−/−</sup> Mice |
| title_sort | poloxamer 407 induces hypertriglyceridemia but decreases atherosclerosis in ldlr sup sup mice |
| topic | poloxamer 407 atherogenesis hypertriglyceridemia foamy monocytes lipid metabolism monocyte phenotype |
| url | https://www.mdpi.com/2073-4409/11/11/1795 |
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