Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart

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.

DJ-1: A promising therapeutic candidate for ischemia-reperfusion injury

“…The explored approaches include the use of superoxide dismutases and relative mimetics [ 103 , [114] , [115] , [116] ], the mitochondrially targeted antioxidant MitoQ [ 102 , 117 , 118 ], N-acetylcysteine [ 119 , 120 ], metformin [ 121 , 122 ], which also acts as a weak complex I inhibitor [ 123 ], and the administration of natural compounds, such as vitamin C [ 124 ]. In addition, recent studies have reported the cardioprotective potential of a mitochondrially targeted MGO and GO scavenger, referred to as MitoGamide, which might be a future promising candidate for IR therapy [ 125 , 126 ]. Besides these compounds in the antioxidant field, interesting insights have been obtained from studies involving the multifaceted protein DJ-1, which is gaining more and more attention as a protective player in response to IR injury.…”

Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide

“…MitoGamide ( Figure 1 a) was synthesized as previously described [ 30 ]. At 6 weeks of age, male mice of both genotypes were randomly assigned to receive either vehicle (10% ethanol in water) or MitoGamide (10 mg/kg) by daily oral gavage ( Figure 1 b).…”

“…MitoGamide (10 mg/kg) was given to mice ( n = 3) by oral gavage, then its contents in the heart, liver, and kidney were measured by LC-MS/MS, as previously described [ 30 ].…”

“…However, MitoG is susceptible to oxidation and short lived. MitoGamide is a longer-lived analogue of MitoG and has been shown to be therapeutically relevant as it is protective in diabetic cardiomyopathy [ 29 , 30 ]. The current study aimed to ascertain if renoprotection could be achieved in the same mouse model using MitoGamide and explored the effects of this compound on restoring mitochondrial homeostasis and downstream signaling in the kidney.…”

Skeletal Muscle Mitochondrial Dysfunction and Oxidative Stress in Peripheral Arterial Disease: A Unifying Mechanism and Therapeutic Target

“…Several naturally occurring substances, including co-enzyme Q, idebenone, and dimethylglycine, have been demonstrated to improve mitochondrial ATP synthesis in patients with various mitochondrial disorders [ 156 , 157 , 158 , 159 ]. Additional compounds have been generated to reduce ROS production or directly scavenge ROS to reduce the burden of oxidative stress associated with mitochondrial pathologies [ 160 , 161 , 162 , 163 , 164 ]. Given that oxidative stress and impairment of oxidative phosphorylation are clearly present in the human PAD skeletal muscle, mitochondrial-targeted therapies may be an untapped area of therapeutic investigation.…”