Confirmation of the cardioprotective effect of MitoGamide in the diabetic heart

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2020-12-01
Author
Park, Min
Nishimura, Takanori
Baeza-Garza, Carlos D.
Caldwell, Stuart T.
Boon Li Pun, Pamela
Prag, Hiran A.
Young, Tim
Sauchanka, Olga
Logan, Angela
Forkink, Marleen
Gruszczyk, Anja V.
Prime, Tracy A.
Arndt, Sabine
Naudí i Farré, Alba
Pamplona Gras, Reinald
Coughlan, Melinda T.
Tate, Mitchel
Ritchie, Rebecca H.
Caicci, Federico
Kaludercic, Nina
Lisa, Fabio Di
Smith, Robin A. J.
Hartley, Richard C.
Murphy, Michael P.
Krieg,Thomas
Suggested citation
Park, Min; Nishimura, Takanori; Baeza-Garza, Carlos D.; Caldwell, Stuart T.; Boon Li Pun, Pamela; Prag, Hiran A.; ... Krieg,Thomas. (2020) . Confirmation of the cardioprotective effect of MitoGamide in the diabetic heart. Cardiovascular Drugs and Therapy, 2020, vol. 34, núm. 6, p. 823-834. https://doi.org/10.1007/s10557-020-07086-7.
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Abstract
Purpose 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. Methods and Results 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. Conclusion 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.
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http://hdl.handle.net/10459.1/70441
DOI
https://doi.org/10.1007/s10557-020-07086-7
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Cardiovascular Drugs and Therapy, 2020, vol. 34, núm. 6, p. 823-834
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cc-by (c) Park et al. 2020
Except where otherwise noted, this item's license is described as cc-by (c) Park et al. 2020