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Auto-amplification of cortisol actions in human carotid atheroma is linked to arterial remodeling and stroke

Authors

  • Hanène Ayari,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
    2. Université de Tunis, Faculté de Médecine, Laboratoire de Biochimie, Tunis, Tunisia
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    • These authors contributed equally to the work.
  • Liliana Legedz,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
    2. Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Hôpital Edouard Herriot, Lyon, France
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    • These authors contributed equally to the work.
  • Pierre Lantelme,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
    2. Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Hôpital Edouard Herriot, Lyon, France
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  • Patrick Feugier,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
    2. Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Hôpital Edouard Herriot, Lyon, France
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  • Jacques Randon,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
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  • Catherine Cerutti,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
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  • Olivier Lohez,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
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  • Jean-Yves Scoazec,

    1. Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Hôpital Edouard Herriot, Lyon, France
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  • Jacques Yuan Li,

    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
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  • Jouda Gharbi-Chihi,

    1. Université de Tunis, Faculté de Médecine, Laboratoire de Biochimie, Tunis, Tunisia
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  • Giampiero Bricca

    Corresponding author
    1. Université Claude Bernard Lyon1, Laboratoire de Pharmacologie EA 4173, INSERM ERI22, Lyon, France
    2. Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Hôpital Edouard Herriot, Lyon, France
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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.

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