Wilson Peter, Morgan James, Funder John W, Fuller Peter J, Young Morag J
Prince Henry's Institute of Medical Research, P.O. Box 5152 Clayton, Melbourne, VIC, Australia.
Clin Sci (Lond). 2009 May;116(9):731-9. doi: 10.1042/CS20080247.
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.
盐皮质激素受体（MR）激活加食盐摄入后，大鼠的冠状动脉、血管及血管周围炎症是心脏纤维化出现的典型先兆。在11β羟类固醇脱氢酶2型（11βHSD2）抑制剂甘珀酸（CBX）加食盐存在的情况下，内源性皮质酮通过MR激活产生类似的炎症反应和组织重塑。此前有研究表明，MR介导的氧化应激是这些反应的原因。因此，在本研究中我们推测，当11βHSD2被抑制时，血管壁中与未受保护的MR结合的内源性皮质酮可能同样会增加氧化应激的早期生物标志物。切除单侧肾脏的大鼠分别给予脱氧皮质酮（DOC）、CBX或CBX加MR拮抗剂依普利酮（EPL），同时饮用0.9%的盐水，持续4、8或16天。切除单侧肾脏并饮用0.9%盐水8天的大鼠作为对照。4天后，DOC和CBX均增加了巨噬细胞浸润以及NADPH氧化酶p22（phox）亚基的mRNA表达，而CBX增加了NOX2（gp91（phox））亚基的表达，DOC则未增加。两种处理方式下，内皮型一氧化氮合酶（eNOS）的mRNA表达从4天起均显著下降，而诱导型一氧化氮合酶（iNOS）的mRNA水平在DOC或CBX处理16天后升高；EPL的共同给药抑制了所有对CBX的反应。在这个时间进程中所表征的反应发生在心脏肥大或纤维化出现可测量增加之前。本研究结果支持以下假设：在CBX存在的情况下，内源性皮质酮可激活血管MR，在纤维化发生之前就产生炎症和氧化组织反应；两种MR配体诱导不同但重叠的基因表达模式；NOX2亚基水平的升高似乎并非MR介导的炎症和纤维化反应充分表达所必需。
