title: Mutual amplification of corticosteroids and angiotensin systems in human vascular smooth muscle cells and carotid atheroma.
abstract: The involvement of the renin-angiotensin-aldosterone system (RAAS) and cortisol in increased cardiovascular risk is well known. If numerous relationships between RAAS and corticosteroids have been described, their interactions within the arterial wall, especially during the transdifferentiation of vascular smooth muscle cells (VSMCs) and the atheroma formation, are not established. Here, we clarified the relationships between mRNA levels of corticosteroid and angiotensin system components using cortisol, fludrocortisone, and angiotensin II treatments of cultured VSMCs maintained in a contractile phenotype or induced to a lipid storing phenotype. We then determined the quantitative relationships between the mRNA content of these components measured with reverse transcription polymerase chain reaction (RT-PCR), in the atheroma plaque and nearby macroscopically intact tissue (MIT) from 27 human carotid endarterectomy samples. In both VSMC phenotypes, cortisol markedly increased both angiotensinogen (AGT) and AT1-receptor (AT1R) mRNA levels. These effects of cortisol were mediated via glucocorticoid receptor-α (GRα) without any illicit activation of the mineralocorticoid receptor (MR). Angiotensin II increased GRα, 11βHSD1, CYP11B1, as well as CYP11B2 mRNAs and decreased AT1R in contractile VSMC; only GRα and CYP11B2 were increased in lipid storing VSMCs, while MR and AGT mRNAs decreased. In endarterectomy specimens, positive correlations between mRNA levels of AGT and aldosterone synthase or 11βHSD1 in MIT and of AT1R and MR in atheroma were detected. The arterial tissue angiotensin system is a target for local glucocorticoids and arterial glucocorticoids for angiotensin II. Both systems appear activated in lipid storing VSMCs and strongly correlated in vivo, and their mutual amplification may contribute to the development of atheroma.
  
  
  CONCLUSIONS
  Cortisol increases angiotensin II signaling in VSMCs via GRα. Angiotensin II stimulates cortisol signaling through increased GRα and 11β-HSD1. Corticoid and angiotensin receptors are strongly correlated in the arterial wall. These correlations are maintained at different stages of atheroma development. An auto-amplification loop between angiotensin and cortisol signaling favors atherogenesis.
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.|Faculté de Médecine de Tunis, Laboratoire de Biochimie, Tunis, Tunisia.
authors.forename: Hanène
authors.initials: H
authors.lastname: Ayari
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Liliana
authors.initials: L
authors.lastname: Legedz
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cerutti
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lantelme
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Feugier
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Gustin
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lohez
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Nehme
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France.
authors.forename: Jacques Yuan
authors.initials: JY
authors.lastname: Li
authors.affiliation: Faculté de Médecine de Tunis, Laboratoire de Biochimie, Tunis, Tunisia.
authors.forename: Jouda
authors.initials: J
authors.lastname: Gharbi-Chihi
authors.affiliation: Hôpital Nord Ouest, Villefranche, Université Lyon1, INSERM, ERI22, 8 Avenue Rockefeller, EA 4173, Lyon, France. giampiero.bricca@inserm.fr.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Bricca
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D000809:Angiotensins / Q000378:metabolism*; D002339:Carotid Arteries / Q000473:pathology*; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D005438:Fludrocortisone / Q000737:chemistry; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D000809:Angiotensins; D008055:Lipids; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D005438:Fludrocortisone; D006854:Hydrocortisone
keywords: Adipocyte; Angiotensin; Artery; Atherosclerosis; Glucocorticoids; Lipid storage; Mineralocorticoids; Nuclear receptors; Transdifferentiation; Type 2 diabetes
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