N-methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism.
N-methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism.
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DOI：
10.1016/j.ehj.2004.05.003
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发表时间：
2004-07
影响因子：
39.3
通讯作者：
Kazuhiro Yamamoto;Yoshito Takahashi;T. Mano;Y. Sakata;N. Nishikawa;Junichi Yoshida;Y. Oishi;M. Hori;T. Miwa;S. Inoue;T. Masuyama
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文献类型：
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作者：
Kazuhiro Yamamoto;Yoshito Takahashi;T. Mano;Y. Sakata;N. Nishikawa;Junichi Yoshida;Y. Oishi;M. Hori;T. Miwa;S. Inoue;T. Masuyama
目的心室纤维化是由多种效应物慢性激活磷脂酶D（PLD）而引起的，并在心血管疾病中引起心功能不全和心力衰竭。由于乙醇胺是一种产品的PLD，我们假设，一个类似物的乙醇胺，N-甲基乙醇胺（MEA），通过负反馈机制，减少PLD的活性，抑制胶原蛋白的积累，从而防止器官功能障碍。方法和resultsIn人成纤维细胞1-丁醇抑制胶原蛋白的合成和增强胶原酶的生产，但异丁醇没有。这表明PLD在胶原合成和降解中起着重要作用。在成纤维细胞中，MEA剂量依赖性地降低PLD活性，抑制胶原合成和增强胶原酶的产生。在使用Dahl-Iwai盐敏感大鼠的高血压心力衰竭模型中，PLD活性随着进行性心室纤维化而增加，导致心肌硬化和明显的心力衰竭。然而，长期给予MEA并没有显著降低血压，但降低了PLD活性和胶原含量，抑制了胶原基因表达，从而防止了心肌硬化和血液动力学恶化。MEA也衰减心室肥大，另一个有害的结构alternation.ConclusionMEA可能会产生治疗效果的心脏疾病，由于心室纤维化，通过抑制PLD活性和调制的纤维化途径，即使没有缓解机械应力。
AimVentricular fibrosis is promoted by many effectors that chronically activate phospholipase D (PLD), and induces cardiac dysfunction and heart failure in cardiovascular diseases. Since ethanolamine is a product of PLD, we hypothesised that an administration of an analogue of ethanolamine,N-methylethanolamine (MEA), decreases PLD activity through a negative feedback mechanism, suppresses collagen accumulation, and thus prevents organ dysfunction.Methods and resultsIn human fibroblasts 1-butanol inhibited collagen synthesis and enhanced collagenase production, but iso-butanol did not. These indicate crucial roles of PLD in collagen synthesis and degradation. In fibroblasts, MEA dose-dependently decreased PLD activity, inhibited collagen synthesis and enhanced collagenase production. In a hypertensive heart failure model using Dahl–Iwai salt-sensitive rats, PLD activity increased with progressive ventricular fibrosis, leading to myocardial stiffening and overt heart failure. Long-term administration of MEA did not significantly decrease blood pressure, however, but decreased PLD activity and collagen content with inhibited gene expression of collagens, leading to the prevention of myocardial stiffening and haemodynamic deterioration. MEA also attenuated ventricular hypertrophy, another detrimental structural alteration.ConclusionMEA may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of PLD activity and modulation of the fibrosis pathway even without relief from mechanical stress.