title: Leukocytosis and enhanced susceptibility to endotoxemia but not atherosclerosis in adrenalectomized APOE knockout mice.
abstract: Hyperlipidemic apolipoprotein E (APOE) knockout mice show an enhanced level of adrenal-derived anti-inflammatory glucocorticoids. Here we determined in APOE knockout mice the impact of total removal of adrenal function through adrenalectomy (ADX) on two inflammation-associated pathologies, endotoxemia and atherosclerosis. ADX mice exhibited 91% decreased corticosterone levels (P<0.001), leukocytosis (WBC count: 10.0 ± 0.4 x 10E9/L vs 6.5 ± 0.5 x 10E9/L; P<0.001) and an increased spleen weight (P<0.01). FACS analysis on blood leukocytes revealed increased B-lymphocyte numbers (55 ± 2% vs 46 ± 1%; P<0.01). T-cell populations in blood appeared to be more immature (CD62L+: 26 ± 2% vs 19 ± 1% for CD4+ T-cells, P<0.001 and 58 ± 7% vs 47 ± 4% for CD8+ T-cells, P<0.05), which coincided with immature CD4/CD8 double positive thymocyte enrichment. Exposure to lipopolysaccharide failed to increase corticosterone levels in ADX mice and was associated with a 3-fold higher (P<0.05) TNF-alpha response. In contrast, the development of initial fatty streak lesions and progression to advanced collagen-containing atherosclerotic lesions was unaffected. Plasma cholesterol levels were decreased by 35% (P<0.001) in ADX mice. This could be attributed to a decrease in pro-atherogenic very-low-density lipoproteins (VLDL) as a result of a diminished hepatic VLDL secretion rate (-24%; P<0.05). In conclusion, our studies show that adrenalectomy induces leukocytosis and enhances the susceptibility for endotoxemia in APOE knockout mice. The adrenalectomy-associated rise in white blood cells, however, does not alter atherosclerotic lesion development probably due to the parallel decrease in plasma levels of pro-atherogenic lipoproteins.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.forename: Vanessa
authors.initials: V
authors.lastname: Frodermann
authors.forename: Tim
authors.initials: T
authors.lastname: van den Aardweg
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
mesh_terms: D000315:Adrenalectomy / Q000009:adverse effects*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology*; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D019446:Endotoxemia / Q000097:blood / Q000209:etiology*; D004909:Erythrocyte Indices; D005260:Female; D007958:Leukocyte Count; D007964:Leukocytosis / Q000097:blood / Q000209:etiology*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D008074:Lipoproteins; D003345:Corticosterone