Cytochrome P450-derived metabolites of docosahexaenoic acid or arachidonic acid enhance contractility of cultured rat cardiomyocytes: a pilot study

Regenerative medicine is perceived as a new treatment for severe heart disease. However, cell-based regenerative therapy for cardiac tissue primarily contributes through its paracrine effect, with limited direct impact on contractile force. We have previously found that docosahexaenoic (DHA) and arachidonic (AA) acid could improve the contractility of cultured cardiomyocytes. On the other hand, the beneficial effect of their metabolites produced by cytochrome P450 (CYP) has not been clarified yet because CYPs are abundantly expressed in the liver. In the present study, we evaluated the effects of CYP-derived metabolite of DHA or AA on contractility of cultured rat cardiomyocytes. The cardiomyocytes were cultured in the medium which were supplemented each metabolite for 4 days, and then we evaluated contractile fraction, beat rate, and contraction velocity under a microscope. In addition, we fabricated collagen gel-based myocardial tissue, cultured them for 24 h in the metabolites-containing medium, and measured the contractile force generated by the tissue. 19,20-epoxydocosapentaenoic acid (EpDPE) enhanced both contractile fraction and contraction velocity of cardiomyocytes, whereas 22-hydroxydocosahexaenoic and 8,9-eicosatrienoic acids increased contractile fraction only, and 18- and 20-hydroxyeicosatetraenoic acids increased contraction velocity. Furthermore, 19,20-EpDPE tended to increase the contractile force of myocardial tissue, whereas none of the other metabolites produced a comparable effect. These results indicate that some DHA and AA metabolites can improve contractile fraction as well as contraction velocity of cardiomyocytes in culture; however, an appreciable contribution to contractile force within 24 h is not anticipated.