Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart

Min Park,Tim Young,Richard C Hartley,Reinald Pamplona,Rebecca H Ritchie,Marleen Forkink,Nina Kaludercic,Hiran A Prag,Angela Logan,Tracy A Prime,Carlos D Baeza-Garza,Michael P Murphy,Federico Caicci,Anja V Gruszczyk,Melinda T Coughlan,Stuart T Caldwell,Fabio Di Lisa,Mitchel Tate,Pamela Boon Li Pun,Olga Sauchanka,Sabine Arndt,Takanori Nishimura,Alba Naudí ,Robin A.j Smith ,Thomas Krieg

doi:10.1007/s10557-020-07086-7

Abstract

PurposeHFpEF (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 ResultsA 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.ConclusionOur 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.

Highlights

Heart failure with preserved ejection fraction (HFpEF) is an early cardiac manifestation found in young diabetic individuals, whereas heart failure with reduced ejection fraction (HFrEF) develops predominantly in older age groups [1]
When we treated Akita mice with MitoGamide, we found that it decreased the development of diastolic dysfunction, raising the prospect that mitochondria-targeted therapies may help in treating diabetic cardiomyopathy
To validate the protective effects of MitoGamide described previously, we first independently confirmed the phenotype of Akita mice

Summary

Introduction

Heart failure with preserved ejection fraction (HFpEF) is an early cardiac manifestation found in young diabetic individuals, whereas heart failure with reduced ejection fraction (HFrEF) develops predominantly in older age groups [1]. Currently available anti-diabetic drugs are of limited efficacy against both HFpEF and HFrEF, and the associated increase in mortality [2]. A major impediment to developing drugs for HFpEF is the lack of preclinical animal models that closely replicate the human pathology. Methylglyoxal and glyoxal are a major cause of the accumulation of protein glycation and of advanced glycation endproducts (AGEs) in diabetes [4]. These modifications are thought to disrupt protein function and are implicated in the pathogenesis of diabetes and in its related cardiovascular complications [4, 5]. The pathological role of dicarbonyl glycation has been demonstrated using pharmacological inhibitors, or by altering expression of the dicarbonyl detoxifying enzyme, glyoxalase I (Glo I) [8,9,10]

Methods

Results

Conclusion