Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart.
Coronary, vascular and perivascular inflammation in rats following MR (mineralocorticoid receptor) activation plus salt are well-characterized precursors for the appearance of cardiac fibrosis. Endogenous corticosterone, in the presence of the 11betaHSD2 (11beta hydroxysteroid dehydrogenase type 2) inhibitor CBX (carbenoxolone) plus salt, produces similar inflammatory responses and tissue remodelling via activation of MR. MR-mediated oxidative stress has previously been suggested to account for these responses. In the present study we thus postulated that when 11betaHSD2 is inhibited, endogenous corticosterone bound to unprotected MR in the vessel wall may similarly increase early biomarkers of oxidative stress. Uninephrectomized rats received either DOC (deoxycorticosterone), CBX or CBX plus the MR antagonist EPL (eplerenone) together with 0.9% saline to drink for 4, 8 or 16 days. Uninephrectomized rats maintained on 0.9% saline for 8 days served as controls. After 4 days, both DOC and CBX increased both macrophage infiltration and mRNA expression of the p22(phox) subunit of NADPH oxidase, whereas CBX, but not DOC, increased expression of the NOX2 (gp91(phox)) subunit. eNOS [endothelial NOS (NO synthase)] mRNA expression significantly decreased from 4 days for both treatments, and iNOS (inducible NOS) mRNA levels increased after 16 days of DOC or CBX; co-administration of EPL inhibited all responses to CBX. The responses characterized over this time course occurred before measurable increases in cardiac hypertrophy or fibrosis. The findings of the present study support the hypothesis that endogenous corticosterone in the presence of CBX can activate vascular MR to produce both inflammatory and oxidative tissue responses well before the onset of fibrosis, that the two MR ligands induce differential but overlapping patterns of gene expression, and that elevation of NOX2 subunit levels does not appear necessary for full expression of MR-mediated inflammatory and fibrogenic responses.
Wilson
Peter
P
Prince Henry's Institute of Medical Research, P.O. Box 5152 Clayton, Melbourne, VIC, Australia.
Morgan
James
J
Funder
John W
JW
Fuller
Peter J
PJ
Young
Morag J
MJ
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D006332:Cardiomegaly / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009205:Myocarditis / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; C506897:Spp1 protein, rat; D053495:Osteopontin; D009569:Nitric Oxide; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone