Aldosterone Inhibits Antifibrotic Factors in Mouse Hypertensive Heart
Aldosterone Inhibits Antifibrotic Factors in Mouse Hypertensive Heart
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DOI：
10.1161/hypertensionaha.111.190512
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发表时间：
2012-06-01
期刊：
影响因子：
8.3
通讯作者：
Delcayre, Claude
中科院分区：
文献类型：
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作者：
Azibani, Feriel;Benard, Ludovic;Delcayre, Claude
肾素-血管紧张素-醛固酮系统参与动脉高血压相关的心血管重塑。在这种情况下，心脏纤维化的发展是由于促纤维化和抗纤维化途径之间的不平衡所致，其中醛固酮的作用尚未确定。为了确定心内醛固酮在高血压期间心肌纤维化发展中的作用，我们使用了心脏醛固酮增多症（AS）和全身性高血压（Ren）的双转基因模型（AS-Ren）。 9月龄高血压小鼠出现心脏纤维化，醛固酮增多症加剧了纤维化水平。与野生型和 AS 小鼠相比，Ren 和 AS-Ren 小鼠的结缔组织生长因子和转化生长因子-β 1 的 mRNA 水平分别相似地增加。醛固酮增多症合并高血压有利于心脏巨噬细胞（CD68+细胞）浸润，并提高单核细胞趋化蛋白1、骨桥蛋白和半乳糖凝集素3的mRNA水平。有趣的是，在AS-Ren小鼠中，高血压引起的骨形态发生蛋白4 mRNA和蛋白水平的增加被显着抑制，B型利尿钠 肽表达减弱。盐皮质激素受体拮抗剂依普利农可恢复 AS-Ren 小鼠中 B 型利钠肽和骨形态发生蛋白 4 的水平，并降低 CD68 和半乳糖凝集素 3 的水平。最后，当野生型和 AS 小鼠中通过输注血管紧张素 II 诱导高血压时，mRNA 谱分别与 Ren 和 AS-Ren 小鼠中观察到的没有差异。醛固酮诱导的 B 型利钠肽和骨形态发生蛋白 4 表达的抑制在体外在新生小鼠心肌细胞中得到证实。总而言之，我们证明，在心脏水平上，醛固酮增多症通过 2 种盐皮质激素受体依赖性机制、激活炎症/半乳糖凝集素 3 诱导的纤维化和抑制抗纤维化因子（B 型利钠肽和骨形态发生蛋白 4），加重高血压诱导的纤维化。 （高血压。2012；59：1179-1187。）。在线数据补充
The renin-angiotensin-aldosterone system is involved in the arterial hypertension-associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-beta 1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4). (Hypertension. 2012;59:1179-1187.). Online Data Supplement