Daily injection of Poloxamer 407 induced severe hypertriglyceridemia but unexpectedly decreased atherosclerosis in Ldlr−/− mice compared to saline control.
Does daily injection of poloxamer 407 alter atherosclerosis and monocyte migration in male Ldlr−/− mice fed a Western diet?
In a mouse model of diet-induced atherogenesis, P407-induced hypertriglyceridemia unexpectedly reduced atherosclerosis, potentially by depleting circulating CD36+ monocytes.
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.
Peng et al. (Mon,) conducted a other in Atherosclerosis and Hypertriglyceridemia. Poloxamer 407 (P407) vs. Saline control was evaluated on Atherosclerosis, monocyte phenotypes, and monocyte migration into atherosclerotic lesions. Daily injection of Poloxamer 407 induced severe hypertriglyceridemia but unexpectedly decreased atherosclerosis in Ldlr−/− mice compared to saline control.