The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published 15 August 2005. doi:10.1084/jem.20050119
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 4, 517-527
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ARTICLE

 11ß-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice

Anne Hermanowski-Vosatka, James M. Balkovec, Kang Cheng, Howard Y. Chen, Melba Hernandez, Gloria C. Koo, Cheryl B. Le Grand, Zhihua Li, Joseph M. Metzger, Steven S. Mundt, Heather Noonan, Christian N. Nunes, Steven H. Olson, Bill Pikounis, Ning Ren, Nancy Robertson, James M. Schaeffer, Kashmira Shah, Martin S. Springer, Alison M. Strack, Matthias Strowski, Kenneth Wu, TsueiJu Wu, Jianying Xiao, Bei B. Zhang, Samuel D. Wright, and Rolf Thieringer

Merck Research Laboratories, Merck and Company, Rahway, NJ 07065

CORRESPONDENCE Anne Hermanowski-Vosatka: anne_vosatka{at}merck.com

The enzyme 11ß–hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11ß-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11ß-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11ß-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11ß-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.

Abbreviations used: apoE, apolipoprotein E; BID, bis in die; DIO, diet-induced obesity; EWAT, epididymal white adipose tissue; GC, glucocorticoid; HDL, high density lipoprotein; HF, high fat; HPA, hypothalamic-pituitary-adrenal; HSD, hydroxysteroid dehydrogenase; MCP, monocyte chemoattractant protein; PD, pharmacodynamic; PO, per os; STZ, streptozotocin.

M. Strowski's present address is Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany.


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