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The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart
journal contributionposted on 2020-12-17, 05:26 authored by Mitchel Tate, Gavin C Higgins, Miles J De Blasio, Runa Lindblom, Darnel Prakoso, Minh Deo, Helen Kiriazis, Min Park, Carlos D Baeza-Garza, Stuart T Caldwell, Richard C Hartley, Thomas Krieg, Michael P Murphy, Melinda T Coughlan, Rebecca RitchieRebecca Ritchie
© 2019, The Author(s). Purpose: Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy. Methods: Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography. Results: Akita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e′/a′ ratio and E/e′ ratio. Conclusions: Our findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.
Rebecca H Ritchie was supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (ID1059660). Melinda T Coughlan was a recipient of a Career Development Award from JDRF Australia, the recipient of the Australian Research Council Special Research Initiative in Type 1 Juvenile Diabetes. This work was funded by a grant from the National Health and Medical Research Council of Australia. This work was also supported in part by the Victorian Government's Operational Infrastructure Support Program. Work in the Murphy lab is supported by the Medical Research Council UK (MC_U105663142) and by a Wellcome Trust Investigator award (110159/Z/15/Z); work in the Hartley lab was supported by the Biotechnology and Biological Sciences Research Council Grant (BB/I012826/1), Wellcome Trust Investigator award (110158/Z/15/Z) and a Consejo Nacional de Ciencia y Technologia studentship (to CBG).
JournalCardiovascular Drugs and Therapy
Pagination6p. (p. 669-674)
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicineCardiac & Cardiovascular SystemsPharmacology & PharmacyCardiovascular System & CardiologyDiabetesHeartDiabetic cardiomyopathyMethylglyoxalCARDIOMYOPATHYMECHANISMSGLYCATIONMitochondria, HeartAnimalsMice, Inbred C57BLDisease Models, AnimalPyruvaldehydeAmidesBenzamidesDiphenylamineInsulinCardiotonic AgentsVentricular Function, LeftMutationMaleDiabetic CardiomyopathiesCardiovascular System & Hematology