title: Adrenalectomy stimulates the formation of initial atherosclerotic lesions: reversal by adrenal transplantation.
abstract: Long-term changes in the secretion of immunosuppressive adrenal-derived glucocorticoid hormones influence cardiovascular disease risk. Here we determined the consequences of changes in adrenal steroid metabolism for the development of atherosclerotic lesions in mice. Atherosclerosis-susceptible low-density-lipoprotein (LDL) receptor knockout mice were subjected to adrenalectomy (ADX) or a control (SHAM) operation and subsequently fed an atherogenic diet for 4 weeks. Atherogenic diet feeding raised plasma corticosterone levels in SHAM mice, but not adrenalectomized mice, resulting in an 83% lower (P<0.01) corticosterone level in adrenalectomized mice. Adrenalectomy was associated with a respectively 22% and 29% lower plasma level of cholesterol and triglycerides. In contrast, white blood cell counts were increased 2-fold (P<0.01) in adrenalectomized mice, which could be attributed to a significant 2.1- to 2.6-fold rise in lymphocyte (P<0.05) and monocyte (P<0.05) numbers. Probably as a result of the enhanced systemic inflammatory status, adrenalectomy was associated with a higher susceptibility for diet-induced atherosclerosis (321±18×10(3) μm(2) for ADX vs 240±31×10(3) μm(2) for SHAM; P<0.05) not withstanding the lowered cholesterol levels. Restoring adrenocortical steroid secretion - but not adrenal medulla function - and the associated downstream glucocorticoid receptor signaling in adrenalectomized mice through adrenal transplantation induced a reversal of the adrenalectomy-associated rise in white blood cell numbers, plasma monocyte chemoattractant protein 1 (MCP-1) levels, and atherosclerotic lesion development (lesion size in transplanted mice: 258±34×10(3) μm(2); P<0.05 vs ADX). In conclusion, our studies show that adrenal-derived steroids protect against the development of initial atherosclerotic lesions in LDL receptor knockout mice.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, P.O. Box 9502, 2300RA Leiden, The Netherlands.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.forename: Gijs H
authors.initials: GH
authors.lastname: van Puijvelde
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism / Q000637:transplantation*; D000315:Adrenalectomy / Q000009:adverse effects*; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000097:blood; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D011973:Receptors, LDL; D014280:Triglycerides; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D003345:Corticosterone