2.P.20 HMG-CoA reductase and ACAT inhibitors act synergistically to lower plasma cholesterol and limit atherosclerotic lesion formation in the rabbit

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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Disodium ascorbyl phytostanyl phosphate reduces plasma cholesterol concentrations and atherosclerotic lesion formation in apolipoprotein E-deficient mice

Metabolism ◽

10.1053/meta.2003.50084 ◽

2003 ◽

Vol 52 (4) ◽

pp. 425-431 ◽

Cited By ~ 20

Author(s):

Tatjana Lukic ◽

Kishor M. Wasan ◽

Daniela Zamfir ◽

Mohammed H. Moghadasian ◽

P.Haydn Pritchard

Keyword(s):

Apolipoprotein E ◽

Plasma Cholesterol ◽

Atherosclerotic Lesion ◽

Lesion Formation ◽

Deficient Mice ◽

Atherosclerotic Lesion Formation

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Flaxseed reduces plasma cholesterol and atherosclerotic lesion formation in ovariectomized Golden Syrian hamsters

Atherosclerosis ◽

10.1016/j.atherosclerosis.2003.12.032 ◽

2004 ◽

Vol 173 (2) ◽

pp. 223-229 ◽

Cited By ~ 55

Author(s):

Edralin A Lucas ◽

Stanley A Lightfoot ◽

Lisa J Hammond ◽

Latha Devareddy ◽

Dania A Khalil ◽

...

Keyword(s):

Plasma Cholesterol ◽

Atherosclerotic Lesion ◽

Lesion Formation ◽

Syrian Hamsters ◽

Atherosclerotic Lesion Formation

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Abstract 203: Redox Regulation of MKP-1 and the Functional Reprogramming of Monocyte-Derived Macrophages by Metabolic Stress

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.203 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Hong Seok Kim ◽

Sina Tavakoli ◽

Reto Asmis

Keyword(s):

Bone Marrow ◽

Redox Regulation ◽

Plasma Cholesterol ◽

Atherosclerotic Lesion ◽

Metabolic Stress ◽

Blood Monocytes ◽

Lesion Formation ◽

Increased Risk ◽

Atherosclerotic Lesion Formation

Objective: To determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Methods and Results: Transplantation of MKP-1-deficient (MKP KO ) bone marrow into LDL-R -/- (MKP-1 LeuKO ) mice accelerated high fat diet (HFD)-induced atherosclerotic lesion formation. After 12 weeks of HFD feeding, MKP-1 LeuKO mice showed increases in lesion size in both the aortic root and the aorta, despite reduced plasma cholesterol levels. Macrophage content was increased in lesions of MKP-1 LeuKO mice compared to mice that received wt bone marrow. After only 6 weeks on a HFD, the in vivo chemotactic activity of monocytes was already significantly increased in MKP-1 LeuKO mice. Macrophages isolated from MKP KO mice showed impaired autophagy, increased sensitivity to 7-ketocholesterol-induced apoptosis, and IL-4-induced M2 polarization of these macrophages was blocked. Importantly, macrophages in atherosclerotic lesion of MKP-1 LeuKO mice showed increased macrophage apoptosis and decreased autophagy. Metabolic stress in vitro mimicked the functional phenotype of MKP-1 deficiency, and overexpression of MKP-1 protected macrophages from metabolic stress-induced dysfunction and reprogramming. Conclusions: Loss of MKP-1 activity promotes monocyte dysfucntion and the functional reprogramming of monocyte-derived macrophages. MKP-1 deficiency accelerates atherosclerotic lesion formation by hyper-sensitizing monocytes to chemokine-induced recruitment, predisposing macrophages to M1 polarization, impaired autophagy and oxysterol-induced cell death. Reduced MKP-1 levels and activity in blood monocytes may therefore be a sensitive biomarker of increased risk of atherosclerosis.

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