Confirmation of the cardioprotective effect of MitoGamide in the diabetic heart

Park, M. et al. (2020) Confirmation of the cardioprotective effect of MitoGamide in the diabetic heart. Cardiovascular Drugs and Therapy, 34, pp. 823-834. (doi: 10.1007/s10557-020-07086-7) (PMID:32979176)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Hartley, Professor Richard
Authors: Park, M., Nishimura, T., Baeza-Garza, C. D., Caldwell, S. T., Pun, P. B. L., Prag, H. A., Young, T., Sauchanka, O., Logan, A., Forkink, M., Gruszczyk, A. V., Prime, T. A., Arndt, S., Naudi, A., Pamplona, R., Coughlan, M. T., Tate, M., Ritchie, R. H., Caicci, F., Kaludercic, N., Di Lisa, F., Smith, R. A.J., Hartley, R. C., Murphy, M. P., and Krieg, T.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Cardiovascular Drugs and Therapy
ISSN (Online):1573-7241
Published Online:26 September 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cardiovascular Drugs and Therapy 34:pages823–834
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
165401Developing chemical mass spectrometry probes to assess the production of reactive oxygen species in vivoRichard HartleyBiotechnology and Biological Sciences Research Council (BBSRC)BB/I012826/1Chemistry
172617Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZChemistry