Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart.
Min Park; Takanori Nishimura; Carlos D Baeza-Garza; Stuart T Caldwell; Pamela Boon Li Pun; Hiran A Prag; Tim Young; Olga Sauchanka; Angela Logan; Marleen Forkink; Anja V Gruszczyk; Tracy A Prime; Sabine Arndt; Alba Naudi; Reinald Pamplona; Melinda T Coughlan; Mitchel Tate; Rebecca H Ritchie; Federico Caicci; Nina Kaludercic; Fabio Di Lisa; Robin A J Smith; Richard C Hartley; Michael P Murphy; Thomas Krieg
HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide.A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group.Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.
|Journal||CARDIOVASCULAR DRUGS AND THERAPY|
|Published||01 Dec 2020|