Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice

Previous studies have demonstrated that macrophage-derived apolipoprotein E (apoE) reduces atherosclerotic lesion formation in lean apoE-deficient (−/−) mice. apoE has also been demonstrated to play a role in adipocyte differentiation and lipid accumulation. Because the prevalence of obesity has grown to epidemic proportions, we sought to determine whether macrophage-derived apoE could impact atherosclerotic lesion formation or adipose tissue expansion and inflammation in obese apoE−/− mice. To this end, we transplanted obese leptin-deficient ( ob/ ob) apoE−/− mice with bone marrow from either ob/ ob;apoE−/− or ob/ ob;apoE+/+ donors. There were no differences in body weight, total body adipose tissue, or visceral fat pad mass between recipient groups. The presence of macrophage-apoE had no impact on adipose tissue macrophage content or inflammatory cytokine expression. Recipients of apoE+/+ marrow demonstrated 3.7-fold lower plasma cholesterol ( P < 0.001) and 1.7-fold lower plasma triglyceride levels ( P < 0.01) by 12 wk after transplantation even though apoE was present in plasma at concentrations <10% of wild-type levels. The reduced plasma lipids reflected a dramatic decrease in very low density lipoprotein and a mild increase in high-density lipoprotein levels. Atherosclerotic lesion area was >10-fold lower in recipients of ob/ ob;apoE+/+ marrow ( P < 0.005). Similar results were seen in leptin receptor-deficient ( db/ db) apoE−/− mice. Finally, when bone marrow transplantation was performed in 4-mo-old ob/ ob;apoE−/− and db/ db;apoE−/− mice with preexisting lesions, recipients of apoE+/+ marrow had a 2.8-fold lower lesion area than controls ( P = 0.0002). These results demonstrate that macrophage-derived apoE does not impact adipose tissue expansion or inflammatory status; however, even very low levels of macrophage-derived apoE are capable of reducing plasma lipids and atherosclerotic lesion area in obese mice.

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Impact of Macrophage Inflammatory Protein-1α Deficiency on Atherosclerotic Lesion Formation, Hepatic Steatosis, and Adipose Tissue Expansion

PLoS ONE ◽

10.1371/journal.pone.0031508 ◽

2012 ◽

Vol 7 (2) ◽

pp. e31508 ◽

Cited By ~ 17

Author(s):

Arion Kennedy ◽

Marnie L. Gruen ◽

Dario A. Gutierrez ◽

Bonnie K. Surmi ◽

Jeb S. Orr ◽

...

Keyword(s):

Adipose Tissue ◽

Hepatic Steatosis ◽

Atherosclerotic Lesion ◽

Tissue Expansion ◽

Lesion Formation ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein ◽

Atherosclerotic Lesion Formation

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The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

Endocrinology ◽

10.1210/en.2007-0259 ◽

2007 ◽

Vol 148 (9) ◽

pp. 4128-4132 ◽

Cited By ~ 27

Author(s):

Johan Bourghardt ◽

Göran Bergström ◽

Alexandra Krettek ◽

Sara Sjöberg ◽

Jan Borén ◽

...

Keyword(s):

Apolipoprotein E ◽

Low Dose ◽

Hormone Replacement ◽

Atherosclerotic Lesion ◽

Total Serum ◽

High Dose ◽

Lesion Formation ◽

Cholesterol Levels ◽

Deficient Mice ◽

Atherosclerotic Lesion Formation

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17β-estradiol (6 μg/d), or 2-methoxyestradiol [6.66 μg/d (low-dose) or 66.6 μg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

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