title: Auto-amplification of cortisol actions in human carotid atheroma is linked to arterial remodeling and stroke.
abstract: High cortisol and aldosterone levels increase cardiovascular risk, but the respective roles of each hormone within the arterial wall remain controversial. We tested the hypothesis that cortisol production within the arterial wall may contribute to atherosclerotic remodeling and act through illicit activation of the mineralocorticoid receptor (MR). Gene expression studies of the corticoid system components and marker genes of the atherosclerotic process in human carotid atheroma plaque and nearby macroscopically intact tissue (MIT) were considered together with clinical data and compared with pharmacological stimulations of human vascular smooth muscle cells (VSMCs) in contractile or lipid-storing phenotypes. The components of corticoid production and action were present and active within the human carotid wall and VSMCs. Atheroma plaque and lipid-storing VSMCs expressed 11β-hydroxysteroid deshydrogenase-1 (11β-HSD1) at two- to tenfold higher levels than MIT or contractile VSMCs. The 11β-HSD1 expression was stimulated by cortisol and cortisone, especially in lipid-storing VSMCs. MR mRNA level was lower in atheroma and lipid-storing VSMCs and downregulated via MR by fludrocortisone and cortisol. Cortisol upregulated collagen1 and MCP-1 mRNAs via the glucocorticoid receptor (GRα), in both VSMC phenotypes, whereas fludrocortisone stimulated the collagen1 expression only in lipid-storing VSMCs. The GRα mRNA level in MIT was higher in patients with previous stroke and correlated positively with the collagen1 mRNA but negatively with diastolic blood pressure. Local cortisol production by 11β-HSD1, and its action via high parietal GRα could be relevant from the first step of atherosclerotic remodeling and auto-amplify with transdifferentiation of VSMCs during atheroma progression.
authors.affiliation: Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France; Université de Tunis, Faculté de Médecine, Laboratoire de Biochimie, Tunis, Tunisia.
authors.forename: Hanène
authors.initials: H
authors.lastname: Ayari
authors.forename: Liliana
authors.initials: L
authors.lastname: Legedz
authors.forename: Pierre
authors.initials: P
authors.lastname: Lantelme
authors.forename: Patrick
authors.initials: P
authors.lastname: Feugier
authors.forename: Jacques
authors.initials: J
authors.lastname: Randon
authors.forename: Catherine
authors.initials: C
authors.lastname: Cerutti
authors.forename: Olivier
authors.initials: O
authors.lastname: Lohez
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Jacques Yuan
authors.initials: JY
authors.lastname: Li
authors.forename: Jouda
authors.initials: J
authors.lastname: Gharbi-Chihi
authors.forename: Giampiero
authors.initials: G
authors.lastname: Bricca
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D001158:Arteries / Q000378:metabolism*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003348:Cortisone / Q000235:genetics / Q000378:metabolism; D005438:Fludrocortisone / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000235:genetics / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D008055:Lipids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; C411470:glucocorticoid receptor alpha; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005438:Fludrocortisone; D003348:Cortisone; D006854:Hydrocortisone