PREREQUISITE FOR CARDIAC ALDOSTERONE ACTION - MINERALOCORTICOID RECEPTOR AND 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN THE HUMAN HEART
PREREQUISITE FOR CARDIAC ALDOSTERONE ACTION - MINERALOCORTICOID RECEPTOR AND 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN THE HUMAN HEART
复制标题
DOI：
10.1161/01.cir.92.2.175
复制
发表时间：
1995-07-15
期刊：
影响因子：
37.8
通讯作者：
BONVALET, JP
中科院分区：
文献类型：
--
作者：
LOMBES, M;ALFAIDY, N;BONVALET, JP
背景：已有研究表明，醛固酮对心功能有直接影响，尤其是对大鼠心肌肥厚时心肌纤维化的形成有直接影响。醛固酮作用的最初事件需要它与盐皮质激素受体(MR)结合。由于MR对醛固酮和糖皮质激素表现出相似的亲和力，因此MR在体内对醛固酮的选择性需要一种酶-11β-羟基类固醇脱氢酶(11-HSD)的存在，该酶能将糖皮质激素代谢成非活性的衍生物。虽然有证据表明啮齿动物心脏中存在MR，但没有用于人类的数据；此外，心脏11-HSD的存在也存在争议。方法和结果所使用的心脏样本来自非移植患者在心脏手术中取出的组织或用于心脏移植随访的腔内活检组织。用人MR基因的cRNA探针进行原位杂交，用两种特异性的抗MR抗体进行免疫检测，从mRNA和蛋白水平检测MR的表达。11-HSD的催化活性是通过测量心脏样品中氚皮质类固醇的代谢率来确定的。在未移植的心脏中，心肌细胞上存在与整个肾脏相同的原位杂交信号。用抗MR抗体对心肌细胞进行特异性免疫标记证实了MR蛋白的存在。检测心脏11-HSD活性(243+/-26fmol.30分钟(-1)。Mg蛋白(-1))，并依赖于辅因子NAD，而不是NADP，这表明它对应于专门负责MR保护的酶的形式。在表现出严重改变的移植心脏中，MR免疫检测较弱且不规则，没有特异的杂交信号。结论我们的结果表明MR与11-HSD在人心脏中共表达，从而具有直接醛固酮作用所需的细胞机制。
Background It has been proposed that aldosterone exerts direct effects on heart function, most notably on the development of myocardial fibrosis during ventricular hypertrophy in rat. Initial events in aldosterone action entail its binding to mineralocorticoid receptor (MR). Because MR displays similar affinities for aldosterone and glucocorticoids, the in vivo aldosterone selectivity of MR requires the presence of an enzyme, 11 beta-hydroxysteroid dehydrogenase (11-HSD), which metabolizes glucocorticoids into inactive derivatives. Although evidence exists for the presence of MR in rodent heart, no data are available for humans; moreover, the existence of cardiac 11-HSD is controversial.Methods and Results The heart samples used originated from tissue removed during cardiac surgery in nontransplant patients or from endocavitary biopsies done for the follow-up of heart transplantation. The expression of MR was examined at the mRNA and protein level by in situ hybridization with cRNA probes specific for human MR mRNA and by immuno-detection with two specific anti-MR antibodies. 11-HSD catalytic activity was determined by measurement of the metabolic rate of tritiated corticosteroids by cardiac samples. In nontransplanted hearts, an in situ hybridization signal equivalent to that found in the whole kidney was present on cardiomyocytes. Specific immunolabeling of cardiomyocytes with anti-MR antibodies demonstrated the presence of the MR protein. Cardiac 11-HSD activity was detected (243+/-26 fmol . 30 min(-1) . mg protein(-1)) and was dependent on the cofactor NAD, not NADP, suggesting that it corresponds to the form of the enzyme specifically responsible for MR protection. In transplanted hearts that presented severe alterations, MR immunodetection was weaker and irregular, with no specific hybridization signal.Conclusions Our results demonstrate that MR is coexpressed with 11-HSD in human heart, which thus possesses the cellular machinery required for direct aldosterone action.