Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

Atherosclerotic lesion formation is associated with extensive oxidation of unsaturated lipids and the accumulation of lipid oxidation products. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion. Aldehydes generated by oxidized lipids are metabolized by several biochemical pathways, of which aldose reductase (AR)-catalyzed reduction represents a metabolic fate common to both free and phospholipid esterified aldehydes. Herein, we tested the hypothesis that inhibition of AR could aggravate atherosclerotic lesion formation by preventing the removal and the detoxification of aldehydes generated by oxidized lipids. In atherosclerotic lesions of apoE-null mice, AR protein was associated with macrophage-rich regions and its abundance increased with lesion progression. Treatment of 8 week old apoE-null mice with AR inhibitors sorbinil or tolrestat for 4 weeks increased lesion formation in the aortic arch (P<0.01) and the aortic sinus (P<0.01). No change in lesion formation was observed when 24 week old mice were fed AR inhibitors for 12 weeks. To probe the role of AR in atherogenesis further, we generated AR −/− /apoE −/− mice. Lesions of 8 week old AR −/− /apoE −/− mice maintained on high fat diet for 4 or 12 weeks were significantly larger throughout the aortic tree (P<0.01 for both the groups) when compared with age-matched AR +/+ /apoE −/− mice. Lesions in AR −/− /apoE −/− mice exhibited increased collagen (P<0.01) and macrophage content (P<0.01) and a decrease in smooth muscle cells (P<0.01). GC-MS analysis showed that the concentration of AR substrates HNE and hexanal was increased by 2.5–3 fold (P<0.01) in the plasma of AR −/− /apoE −/− mice as compared with AR +/+ /apoE −/− mice. Immunohistochemical analysis showed greater accumulation of protein-HNE adducts in arterial lesions of AR −/− /apoE −/− mice. These observations suggest that AR is up regulated during atherosclerosis and that this protein protects against early stages of atherosclerotic lesion formation by removing aldehydes generated by lipid oxidation.

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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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GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

Molecular Therapy ◽

10.1038/mt.2016.160 ◽

2016 ◽

Vol 24 (11) ◽

pp. 1926-1938 ◽

Cited By ~ 34

Author(s):

Wen Mei ◽

Guangda Xiang ◽

Yixiang Li ◽

Huan Li ◽

Lingwei Xiang ◽

...

Keyword(s):

Apolipoprotein E ◽

Atherosclerotic Lesion ◽

Endothelial Injury ◽

Lesion Formation ◽

Atherosclerotic Lesion Formation

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Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice

Cardiovascular Research ◽

10.1093/cvr/cvv282 ◽

2015 ◽

Vol 110 (1) ◽

pp. 107-117 ◽

Cited By ~ 42

Author(s):

Mizuho Hiramatsu-Ito ◽

Rei Shibata ◽

Koji Ohashi ◽

Yusuke Uemura ◽

Noriyoshi Kanemura ◽

...

Keyword(s):

Apolipoprotein E ◽

Atherosclerotic Lesion ◽

Lesion Formation ◽

Deficient Mice ◽

Atherosclerotic Lesion Formation

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00601.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. E284-E290 ◽

Cited By ~ 13

Author(s):

Robin D. Atkinson ◽

Kimberly R. Coenen ◽

Michelle R. Plummer ◽

Marnie L. Gruen ◽

Alyssa H. Hasty

Keyword(s):

Adipose Tissue ◽

Apolipoprotein E ◽

Plasma Lipids ◽

Atherosclerotic Lesion ◽

Density Lipoprotein ◽

Tissue Expansion ◽

Lower Plasma ◽

Lesion Area ◽

Lesion Formation ◽

Atherosclerotic Lesion Formation

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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