Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients
Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients
复制标题
DOI：
10.1161/01.res.0000187500.24964.7a
复制
发表时间：
2005-10-28
影响因子：
20.1
通讯作者：
Abassi, Z
中科院分区：
文献类型：
--
作者：
Keidar, S;Gamliel-Lazarovich, A;Abassi, Z
醛固酮在充血性心力衰竭（CHF）的病理生理中起重要作用，螺内酯可改善CHF患者的心血管功能和生存率。我们假设盐皮质激素受体阻断剂（MRB）通过减少氧化应激和改变反作用酶血管紧张素转换酶（ACE）和ACE 2之间的平衡来发挥其有益作用。从10例CHF患者接受螺内酯（25 mg/d）治疗前和治疗1个月后获得单核细胞衍生的巨噬细胞。螺内酯治疗显著（P < 0.005）降低了氧化应激，表现为脂质过氧化物含量、超氧离子释放和低密度脂蛋白氧化分别降低了28%、53%和70%。螺内酯使巨噬细胞ACE活性和mRNA表达分别降低47%和53%（P < 0.01），而ACE 2活性和mRNA表达分别增加300%和654%（P < 0.01）。在用依普利酮（200 mg（.）kg（-1）。d（-1））时，心肌ACE 2活性显著升高（P < 0.05），心肌ACE 2活性升高2倍，并被巨噬细胞ACE 2活性升高所抵消。在体外培养的小鼠腹腔巨噬细胞（MPM）中研究了醛固酮拮抗剂的作用机制。250 nmol/L醛固酮使ACE活性和mRNA表达显著增加，但ACE 2活性显著降低。与依普利酮（2 μ mol/L）共处理可减弱上述作用。在从p47敲除小鼠获得的MPM中，其中NADPH氧化酶是无活性的，以及在用NADPH氧化酶抑制剂处理的对照MPM中，醛固酮不增加ACE或减少ACE 2。MRB可降低氧化应激，降低ACE活性，并增加ACE 2活性，表明MRB可能通过增加血管紧张素（1-7）的生成和减少血管紧张素II的形成而发挥保护作用。这些作用至少部分由NADPH氧化酶介导。
Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolactone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocorticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained from 10 patients with CHF before and after 1 month of treatment with spironolactone (25 mg/d). Spironolactone therapy significantly (P < 0.005) reduced oxidative stress, as expressed by reduced lipid peroxide content, superoxide ion release, and low-density lipoprotein oxidation by 28%, 53%, and 70%, respectively. Although spironolactone significantly (P < 0.01) reduced macrophage ACE activity by 47% and mRNA expression by 53%, ACE2 activity and mRNA expression increased by 300% and 654%, respectively. In mice treated for 2 weeks with eplerenone (200 mg (.) kg(-1) . d(-1)), cardiac ACE2 activity significantly (P < 0.05) increased by 2-fold and was paralleled by increased ACE2 activity in macrophages. The mechanism of aldosterone antagonist action was studied in mouse peritoneal macrophages (MPMs) in vitro. Although ACE activity and mRNA were significantly increased by 250 nmol/L aldosterone, ACE2 was significantly reduced. Cotreatment with eplerenone (2 mu mol/L) attenuated these effects. In MPM obtained from p47 knockout mice, where NADPH oxidase is inactive, as well as in control MPMs treated with NADPH oxidase inhibitor, aldosterone did not increase ACE or decrease ACE2. MRB reduced oxidative stress, decreased ACE activity, and increased ACE2 activity, suggesting a protective role for MRB by possibly increasing generation of angiotensin (1-7) and decreasing formation of angiotensin II. These effects are mediated, at least in part, by NADPH oxidase.