In vivo effects of propyl gallate, a novel Ca(2+) sensitizer, in a mouse model of dilated cardiomyopathy caused by cardiac troponin T mutation

Abstract

Aims: We have previously demonstrated that propyl gallate has a Ca(2+) sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca(2+) sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate.

Main methods: We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca(2+) sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca(2+) sensitivity due to a deletion mutation ΔK210 in cardiac troponin T.

Key findings: Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca(2+) sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca(2+) sensitizing action, had no beneficial effects on the DCM mice.

Significance: These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca(2+) sensitivity.

Keywords: Ca(2+) sensitizer; Cardiac troponin T; Dilated cardiomyopathy; Knock-in mice; Propyl gallate.