Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes
Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes
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DOI：
10.1073/pnas.102673599
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Jaisser, F
中科院分区：
文献类型：
--
作者：
Beggah, AT;Escoubet, B;Jaisser, F
心力衰竭是心脏病演变过程中的一个共同特征。在心力衰竭的决定因素中，肾素-血管紧张素-醛固酮系统起着核心作用，并且已经提出拮抗盐皮质激素受体（MR）作为一种治疗策略。在这项研究中，我们使用可诱导的心脏特异性转基因小鼠模型质疑 MR（而不是醛固酮）对心脏功能的作用。我们通过仅在心脏中表达针对小鼠 MR 的反义 mRNA（心肌细胞中靶标未知的转录因子），生成了条件敲除模型。在 2-3 个月内，小鼠在没有高血压或慢性醛固酮增多症的情况下出现严重心力衰竭和心脏纤维化。此外，当 MR 反义 mRNA 表达随后被抑制时，心力衰竭和纤维化是完全可逆的。
Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the renin-angiotensin-aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model. We have generated a conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR, a transcription factor with unknown targets in cardiomyocytes. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism. Moreover, cardiac failure and fibrosis were fully reversible when MR antisense mRNA expression was subsequently suppressed.