Glucocorticoid metabolism in the cardiac interstitium: 11 beta-hydroxysteroid dehydrogenase activity in cardiac fibroblasts.
The interstitial fibrosis seen in the heart and systemic organs in states of primary or secondary mineralocorticoid excess suggests that fibroblasts are responsive to mineralocorticoid. In vitro studies demonstrating increased fibroblast collagen synthesis in response to MC are consonant with this view. The nicotinamide-adenine dinucleotide phosphate(+)-dependent enzyme 11 beta-hydroxysteroid dehydrogenase converts the glucocorticoids corticosterone and cortisol to the inactive metabolites 11-dehydrocorticosterone and cortisone, respectively, conferring mineralocorticoid specificity to the cells within which it is active. We investigated the presence of 11 beta-hydroxysteroid dehydrogenase in sonicates of cultured vascular endothelial cells and cardiac fibroblasts by incubating sonicates for 1 hour in the presence of 5 x 10(-9) mol/L tritiated corticosterone or tritiated cortisol (1 microCi) and using reverse-phase high-performance liquid chromatography coupled to an on-line radioisotope detector for steroid separation and quantitation. Extracts of bovine endothelial cells showed no enzymatic activity with either substrate, whereas extracts of rat cardiac fibroblasts readily converted corticosterone to 11-dehydrocorticosterone, even in the absence of exogenous nicotinamide-adenine dinucleotide phosphate+ (10% conversion). When 5 x 10(-4) mol/L nicotinamide-adenine dinucleotide phosphate+ was added to sonicated fibroblasts, conversion increased to 50%, corresponding to 12 pmol 11-dehydrocorticosterone formed/mg protein. Conversion of cortisol to cortisone was not observed in fibroblast or endothelial cell extracts. Significant levels of corticosterone to 11-dehydrocorticosterone conversion (0.14 pmol/10(6) cells/hour) were detected in intact fibroblasts, but no 11-dehydrogenation of corticosterone was observed in intact endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Slight
S
S
University of Missouri-Columbia, Department of Internal Medicine 65212.
Ganjam
V K
VK
Nonneman
D J
DJ
Weber
K T
KT
D015062:11-Hydroxycorticosteroids / Q000378:metabolism*; D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D005347:Fibroblasts / Q000201:enzymology*; D006854:Hydrocortisone / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015062:11-Hydroxycorticosteroids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003345:Corticosterone; D006854:Hydrocortisone