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Confirmation of the cardioprotective effect of MitoGamide in the diabetic heart
journal contributionposted on 2021-01-15, 05:04 authored by M Park, T Nishimura, CD Baeza-Garza, ST Caldwell, PBL Pun, HA Prag, T Young, O Sauchanka, A Logan, M Forkink, AV Gruszczyk, TA Prime, S Arndt, A Naudi, R Pamplona, MT Coughlan, M Tate, Rebecca RitchieRebecca Ritchie, F Caicci, N Kaludercic, F Di Lisa, RAJ Smith, RC Hartley, MP Murphy, T Krieg
© 2020, The Author(s). 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.
This work was supported by a BHF project grant to TK (PG/15/84/31670), by a Consejo Nacional de Ciencia y Tecnologia studentship to CB-G, by the Medical Research Council UK (MC_U105663142), TAKEDA Pharmaceutical Company Ltd., and a Wellcome Trust Investigator award (110159/Z/15/Z) to MPM, and by a Biotechnology and Biological Sciences Research Council grant (BB/I012826/1) and a Wellcome Trust Investigator award (110158/Z/15/Z) to RCH. Further support was by a National Health and Medical Research Council (NHMRC) of Australia Senior Research Fellowship (APP1059960) to RHR and by the Generalitat of Catalonia, Department of Health (SLT002/16/00250) and Department of Business and Knowledge (2017SGR696) to RP.
JournalCardiovascular Drugs and Therapy
Pagination12p. (p. 823-834)
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Science & TechnologyLife Sciences & BiomedicineCardiac & Cardiovascular SystemsPharmacology & PharmacyCardiovascular System & CardiologyDiabetesHeart failure with preserved ejection fraction (HFpEF)Akita miceAdvanced glycation endproducts (AGE)MitochondriaGLYCATION END-PRODUCTSPRESERVED EJECTION FRACTIONTYPE-1FAILUREMETHYLGLYOXALMITOCHONDRIADYSFUNCTIONLIVERMODELCardiovascular System & Hematology