11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis

Autor: Kay Samuel, Dawn E W Livingstone, Patrick W. F. Hadoke, Jonathan R. Seckl, M. Amine Bouhlel, Zhenguang Zhang, Tak Yung Man, Christopher I. White, Brian R. Walker, Giulia Chinetti-Gbaguidi, Javaid Iqbal, John Savill, Eileen Miller, Ruth Andrew, Katie M. Sullivan, Karen E. Chapman, Tijana Mitić, Bart Staels, Tiina Kipari, Christopher Schrecker, Agnes E. Coutinho
Jazyk: angličtina
Rok vydání: 2013
Předmět:
medicine.medical_specialty
Apolipoprotein B
Adipose tissue
Vascular Cell Adhesion Molecule-1
030209 endocrinology & metabolism
Inflammation
Biochemistry
Research Communications
03 medical and health sciences
Mice
0302 clinical medicine
11β-hydroxysteroid dehydrogenase type 1
Bone Marrow
Risk Factors
Internal medicine
11-beta-Hydroxysteroid Dehydrogenase Type 1
medicine
Genetics
Animals
Molecular Biology
030304 developmental biology
Mice
Knockout
0303 health sciences
biology
glucocorticoids
Monocyte
atherogenesis
Atherosclerosis
3. Good health
Transplantation
Endocrinology
medicine.anatomical_structure
Adipose Tissue
inflammation
Immunology
biology.protein
Bone marrow
medicine.symptom
Glucocorticoid
hormones
hormone substitutes
and hormone antagonists
medicine.drug
inflammation
Biotechnology
Zdroj: The FASEB Journal
Kipari, T, Hadoke, P W F, Iqbal, J, Man, T-Y, Miller, E, Coutinho, A E, Zhang, Z, Sullivan, K M, Mitic, T, Livingstone, D E W, Schrecker, C, Samuel, K, White, C I, Bouhlel, M A, Chinetti-Gbaguidi, G, Staels, B, Andrew, R, Walker, B R, Savill, J S, Chapman, K E & Seckl, J R 2013, ' 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis ', The FASEB Journal, vol. 27, no. 4, pp. 1519-1531 . https://doi.org/10.1096/fj.12-219105
ISSN: 1530-6860
0892-6638
DOI: 10.1096/fj.12-219105
Popis: 11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74–76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.—Kipari, T., Hadoke, P. W. F., Iqbal, J., Man, T. Y., Miller, E., Coutinho, A. E., Zhang, Z., Sullivan, K. M., Mitic, T., Livingstone, D. E. W., Schrecker, C., Samuel, K., White, C. I., Bouhlel, M. A., Chinetti-Gbaguidi, G., Staels, B., Andrew, R., Walker, B. R., Savill, J. S., Chapman, K. E., Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.
Databáze: OpenAIRE
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