title: Adrenalectomy amplifies aldosterone induced injury in cardiovascular tissue: an effect attenuated by adrenally derived steroids.
abstract: Aldosterone induces fibrotic changes in cardiovascular tissues but its effects have usually been demonstrated in models of pre-existing renal injury and/or hypertension. This study tests the hypothesis that aldosterone can directly induce vascular fibrotic changes in the absence of prior renal injury or hypertension. Experiments were conducted in intact or adrenalectomized (ADX) mice. Mice were divided into groups and treated for 1 week with vehicle or aldosterone (8 μg/kg/day)± inhibitor (800 μg/kg/day): CONTROLS, mice treated with aldosterone, ADX-CONTROLS, ADX+corticosterone (CORT 8 μg/kg/day), ADX with aldosterone, ADX with aldosterone plus the mineralocorticoid receptor (MR) antagonist RU-318, ADX with aldosterone+CORT (CORT inhibitor dose), and ADX with aldosterone+11-dehydro-CORT. Aortic smooth muscle to collagen ratio, aorta intimal thickness (μm), heart weight/body weight ratio (mg/gm), and left ventricular collagen (%) were measured. Prior to sacrifice, blood pressures were normal in all animals. Lower dose CORT alone had no effect on any of the variables examined. Aldosterone exposure was associated with extra-cellular matrix accumulation in cardiovascular tissues in intact mice and adrenalectomy exacerbated these effects. RU-318, CORT (inhibitor dose), and 11-deydro-CORT each attenuated the early fibrotic changes induced by aldosterone. In the heart, aldosterone exposure affected all the parameters measured and caused intimal hypercellularity with monocytes adhering to endothelial cells lining coronary vessels. Cultured endothelial cells exposed to aldosterone (10nM) released E-selectin, produced collagen, and promoted monocyte adhesion. These effects were inhibited by RU-318 and 11-deydro-CORT but not by CORT. Thus, adrenalectomy enhances aldosterone induced early fibrotic changes in heart and aorta. Aldosterone initially targets vascular endothelial cells. MR antagonists and 11-dehydro-CORT, an 11β-HSD dehydrogenase end-product, directly attenuate these effects.
authors.affiliation: Division of Kidney Disease and Hypertension, Rhode Island Hospital, The Warren Alpert School of Medicine at Brown University, Providence, RI, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brem
authors.forename: David J
authors.initials: DJ
authors.lastname: Morris
authors.forename: Xiangpo
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaw
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
mesh_terms: D000311:Adrenal Glands / Q000601:surgery; D000315:Adrenalectomy; D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002448:Cell Adhesion / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism
chemical_list: D019040:E-Selectin; D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone; D003094:Collagen; C003552:11-dehydrocorticosterone; D003345:Corticosterone