Adrenalectomy amplifies aldosterone induced injury in cardiovascular tissue: An effect attenuated by adrenally derived steroids

作者：Brem Andrew S; Morris David J; Li Xiangpo; Ge Yan; Shaw Sunil; Gong Rujun^*

来源：Steroids, 2013, 78(3): 347-355.

DOI：10.1016/j.steroids.2012.12.007

• 11 beta-Hydroxysteroid dehydrogenase
• Vascular endothelial cells
• 11-Dehydrocorticosterone
• Mineralocorticoids
• Fibrosis
• Inflammation

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 mu g/kg/day) +/- inhibitor (800 mu g/kg/day): CONTROLS, mice treated with aldosterone, ADX-CONTROLS, ADX + corticosterone (CURT 8 mu g/kg/day), ADX with aldosterone, ADX with aldosterone Plus the mineralocorticoid receptor (MR) antagonist RU-318, ADX with aldosterone + CURT (COAT inhibitor dose), and ADX with aldosterone + 11-dehydro-CORT. Aortic smooth muscle to collagen ratio, aorta intimal thickness (mu m), 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 CURT 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, CURT (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 (10 nM) released E-selectin, produced collagen, and promoted monocyte adhesion. These effects were inhibited by RU-318 and 11-deydro-CORT but not by COAT. 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 11 beta-HSD dehydrogenase end-product, directly attenuate these effects.

• 出版日期2013-3