Kazuhiro, Yamamoto, Yoshito, Takahashi, Toshiaki, Mano, Yasushi, Sakata, Nagahiro, Nishikawa, Junichi, Yoshida, Yuichi, Oishi, Masatsugu, Hori, Shintaro, Inoue, and Tohru, Masuyama
Purpose: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 hypothesized that an administration of an analogue of ethanolamine, N-methylethanolamine (MEA), decreases PLD activity through a negative feedback mechanism, suppresses collagen accumulation, and 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 (HHF) 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, decreased PLD activity and collagen content with inhibited gene expression of collagens, leading to prevention of myocardial stiffening and hemodynamic 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 fibrosis pathway even without a release from mechanical stress.