| First Author | Gaudreault N | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 5 | Pages | e35816 |
| PubMed ID | 22606237 | Mgi Jnum | J:187245 |
| Mgi Id | MGI:5435975 | Doi | 10.1371/journal.pone.0035816 |
| Citation | Gaudreault N, et al. (2012) Macrophage-specific apoE gene repair reduces diet-induced hyperlipidemia and atherosclerosis in hypomorphic Apoe mice. PLoS One 7(5):e35816 |
| abstractText | BACKGROUND: Apolipoprotein (apo) E is best known for its ability to lower plasma cholesterol and protect against atherosclerosis. Although the liver is the major source of plasma apoE, extra-hepatic sources of apoE, including from macrophages, account for up to 10% of plasma apoE levels. This study examined the contribution of macrophage-derived apoE expression levels in diet-induced hyperlipidemia and atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: Hypomorphic apoE (Apoe(h/h)) mice expressing wildtype mouse apoE at approximately 2-5% of physiological levels in all tissues were derived by gene targeting in embryonic stem cells. Cre-mediated gene repair of the Apoe(h/h) allele in Apoe(h/h)LysM-Cre mice raised apoE expression levels by 26 fold in freshly isolated peritoneal macrophages, restoring it to 37% of levels seen in wildtype mice. Chow-fed Apoe(h/h)LysM-Cre and Apoe(h/h) mice displayed similar plasma apoE and cholesterol levels (55.53+/-2.90 mg/dl versus 62.70+/-2.77 mg/dl, n = 12). When fed a high-cholesterol diet (HCD) for 16 weeks, Apoe(h/h)LysM-Cre mice displayed a 3-fold increase in plasma apoE and a concomitant 32% decrease in plasma cholesterol when compared to Apoe(h/h) mice (602.20+/-22.30 mg/dl versus 888.80+/-24.99 mg/dl, n = 7). On HCD, Apoe(h/h)LysM-Cre mice showed increased apoE immunoreactivity in lesional macrophages and liver-associated Kupffer cells but not hepatocytes. In addition, Apoe(h/h)LysM-Cre mice developed 35% less atherosclerotic lesions in the aortic root than Apoe(h/h) mice (167x10(3)+/-16x10(3) microm(2) versus 259x10(3)+/-56x10(3) microm(2), n = 7). This difference in atherosclerosis lesions size was proportional to the observed reduction in plasma cholesterol. CONCLUSIONS/SIGNIFICANCE: Macrophage-derived apoE raises plasma apoE levels in response to diet-induced hyperlipidemia and by such reduces atherosclerosis proportionally to the extent to which it lowers plasma cholesterol levels. |
