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A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function.
Endocrine Reviews ( IF 22.0 ) Pub Date : 2008-02-21 , DOI: 10.1210/er.2007-0030
John M C Connell 1 , Scott M MacKenzie , E Marie Freel , Robert Fraser , Eleanor Davies
Affiliation  

Up to 15% of patients with essential hypertension have inappropriate regulation of aldosterone; although only a minority have distinct adrenal tumors, recent evidence shows that mineralocorticoid receptor activation contributes to the age-related blood pressure rise and illustrates the importance of aldosterone in determining cardiovascular risk. Aldosterone also has a major role in progression and outcome of ischemic heart disease. These data highlight the need to understand better the regulation of aldosterone synthesis and its action. Aldosterone effects are mediated mainly through classical nuclear receptors that alter gene transcription. In classic epithelial target tissues, signaling mechanisms are relatively well defined. However, aldosterone has major effects in nonepithelial tissues that include increased synthesis of proinflammatory molecules and reactive oxygen species; it remains unclear how these effects are controlled and how receptor specificity is maintained. Variation in aldosterone production reflects interaction of genetic and environmental factors. Although the environmental factors are well understood, the genetic control of aldosterone synthesis is still the subject of debate. Aldosterone synthase (encoded by the CYP11B2 gene) controls conversion of deoxycorticosterone to aldosterone. Polymorphic variation in CYP11B2 is associated with increased risk of hypertension, but the molecular mechanism that accounts for this is not known. Altered 11beta-hydroxylase efficiency (conversion of deoxycortisol to cortisol) as a consequence of variation in the neighboring gene (CYP11B1) may be important in contributing to altered control of aldosterone synthesis, so that the risk of hypertension may reflect a digenic effect, a concept that is discussed further. There is evidence that a long-term increase in aldosterone production from early life is determined by an interaction of genetic and environmental factors, leading to the eventual phenotypes of aldosterone-associated hypertension and cardiovascular damage in middle age and beyond. The importance of aldosterone has generated interest in its therapeutic modulation. Disadvantages associated with spironolactone (altered libido, gynecomastia) have led to a search for alternative mineralocorticoid receptor antagonists. Of these, eplerenone has been shown to reduce cardiovascular risk after myocardial infarction. The benefits and disadvantages of this therapeutic approach are discussed.

中文翻译:

终生醛固酮过量:心血管功能醛固酮产生调节改变的长期后果。

高达 15% 的原发性高血压患者醛固酮调节不当;虽然只有少数人患有明显的肾上腺肿瘤,但最近的证据表明盐皮质激素受体激活会导致与年龄相关的血压升高,并说明醛固酮在确定心血管风险方面的重要性。醛固酮在缺血性心脏病的进展和结果中也有重要作用。这些数据强调需要更好地了解醛固酮合成及其作用的调节。醛固酮效应主要通过改变基因转录的经典核受体介导。在经典的上皮靶组织中,信号机制相对明确。然而,醛固酮在非上皮组织中具有重要作用,包括增加促炎分子和活性氧的合成;目前尚不清楚如何控制这些影响以及如何维持受体特异性。醛固酮产生的变化反映了遗传和环境因素的相互作用。尽管环境因素已被很好地理解,醛固酮合成的遗传控制仍然是争论的主题。醛固酮合酶(由 CYP11B2 基因编码)控制脱氧皮质酮向醛固酮的转化。CYP11B2 的多态性变异与高血压风险增加有关,但其分子机制尚不清楚。邻近基因 (CYP11B1) 变异导致的 11β-羟化酶效率改变(脱氧皮质醇转化为皮质醇)可能对改变醛固酮合成控制很重要,因此高血压风险可能反映双基因效应,这是一个概念这将进一步讨论。有证据表明,生命早期醛固酮生成的长期增加是由遗传和环境因素的相互作用决定的,最终导致中年及以后醛固酮相关高血压和心血管损伤的表型。醛固酮的重要性引起了对其治疗调节的兴趣。与螺内酯相关的缺点(性欲改变、男性乳房发育症)导致人们寻找替代的盐皮质激素受体拮抗剂。这些,依普利酮已被证明可降低心肌梗塞后的心血管风险。讨论了这种治疗方法的优点和缺点。
更新日期:2019-11-01
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