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European Heart Journal 2004 25(14):1221-1229; doi:10.1016/j.ehj.2004.05.003
Copyright © 2004 by the European Society of Cardiology.
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Clinical research

N-Methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism

Kazuhiro Yamamotoa,*, Yoshito Takahashib, Toshiaki Manoa,c, Yasushi Sakataa,c, Nagahiro Nishikawaa,c, Junichi Yoshidaa,c, Yuichi Oishib, Masatsugu Horia, Takeshi Miwac, Shintaro Inoueb and Tohru Masuyamaa,1

a Department of Internal Medicine and Therapeutics,Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan
b Basic Research Laboratory, Kanebo Ltd., Odawara, Japan
c Genome Information Research Center, Osaka University, Suita, Japan

* Corresponding author. Tel.: +81-6-6879-6612; fax : +81-6-6879-6613
E-mail address: kazuhiro{at}medone.med.osaka-u.ac.jp

Received 18 October 2003; revised 30 April 2004; accepted 6 May 2004

Abstract

Aim Ventricular 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 results In 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.

Conclusion MEA 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.

Key Words: Collagen • Diastole • Heart failure


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