2. Academic Validation
  3. Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr-/- Mice

Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr-/- Mice

  • Cells. 2022 May 30;11(11):1795. doi: 10.3390/cells11111795.
Xueying Peng 1 2,  Zeqin Lian 2,  Xiao-Yuan Dai Perrard 2,  Yunjie Xiao 2 3,  Jing Ni 2 4,  Veronica O'Brien 2 5,  Henry Dong 6,  Henry J Pownall 7,  Christie M Ballantyne 2,  Huaizhu Wu 2
Affiliations

Affiliations

  • 1 Key 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, China.
  • 2 Department of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USA.
  • 3 College of Natural Science, University of Texas at Austin, Austin, TX 78712, USA.
  • 4 Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
  • 5 Department of Biochemistry, University of Houston, Houston, TX 77204, USA.
  • 6 Department of Pediatrics, Children's Hospital of Pittsburgh UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
  • 7 Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
PMID: 35681489 DOI: 10.3390/cells11111795
Abstract

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-/- mice.

Methods: HTG was induced in male LDLR-/- 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-/- 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+ (also CD11c+), but not CD36- (CD11c-), monocytes showed early increases in lipid accumulation, but the number of CD36+ (not CD36-) monocytes was dramatically decreased afterwards in the circulation until the end of the test. Concurrently, CD36+ (CD11c+) monocyte migration into atherosclerotic lesions was also reduced in mice receiving P407 versus controls.

Conclusions: P407 induced severe HTG, but reduced atherosclerosis, in LDLR-/- mice, possibly because of profound reductions of circulating CD36+ (CD11c+) monocytes, leading to decreased monocyte migration into atherosclerotic lesions.

Keywords

atherogenesis; foamy monocytes; hypertriglyceridemia; lipid metabolism; monocyte phenotype; poloxamer 407.

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