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Intravascular Glucocorticoid Metabolism during Inflammation and Injury in Mice

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Anna R. Dover, Clinical Lecturer, Endocrinology Unit, Centre for Cardiovascular Science, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: Anna.Dover{at}ed.ac.uk.

11ß-Hydroxysteroid dehydrogenases (11ßHSDs) catalyze interconversion of 11-hydroxy-glucocorticoids with inactive 11-keto metabolites. In blood vessel walls, loss of 11ßHSD1 is thought to reduce local glucocorticoid concentrations, reducing the progression of atheroma and enhancing angiogenesis. Conversely, on the basis that 11ßHSD1 is up-regulated approximately 5-fold by inflammatory cytokines in cultured human vascular smooth muscle cells, it has been proposed that increased 11ßHSD1 during vascular inflammation provides negative feedback suppression of inflammation. We aimed to determine whether inflammation and injury selectively up-regulate 11ßHSD1 reductase activity in vitro and in vivo in intact vascular tissue in mice. In isolated mouse aortae and femoral arteries, reductase activity (converting 11-dehydrocorticosterone to corticosterone) was approximately 10-fold higher than dehydrogenase activity and was entirely accounted for by 11ßHSD1 because it was abolished in vessels from 11ßHSD1^–/– mice. Although 11ßHSD1 activity was up-regulated by proinflammatory cytokines in cultured murine aortic smooth muscle cells, no such effect was evident in intact aortic rings in vitro. Moreover, after systemic inflammation induced by ip lipopolysaccharide injection, there was only a modest (18%) increase in 11ß-reductase activity in the aorta and no increase in the perfused hindlimb. Furthermore, in femoral arteries in which neointimal proliferation was induced by intraluminal injury, there was no change in basal 11ßHSD1 activity or the sensitivity of 11ßHSD1 to cytokine up-regulation. We conclude that increased generation of glucocorticoids by 11ßHSD1 in the murine vessel wall is unlikely to contribute to feedback regulation of inflammation.

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				B. R Walker Glucocorticoids and Cardiovascular Disease Eur. J. Endocrinol., November 1, 2007; 157(5): 545 - 559. [Abstract] [Full Text] [PDF]