Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy

Abstract

Aims The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy. Methods The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured. Results Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation. Conclusions Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.

BGP-15 Protects against Oxidative Stress- or Lipopolysaccharide-Induced Mitochondrial Destabilization and Reduces Mitochondrial Production of Reactive Oxygen Species

“…Essentially, the results were comparable to those we obtained with DHR123 (Fig 4A and 4B vs. 4E and 4F). Furthermore, we repeated these experiments in the presence of the mitochondria-targeted antioxidant MitoTEMPO [40]. MitoTEMPO abolished H 2 O 2 -induced ROS production in all groups (Fig 4E and 4F) indicating mitochondrial localization of the BGP-sensitive ROS production.…”

Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting

“…Nonetheless, a recent randomised CHF trial (Q-SYMBIO) indicated that CoQ 10 reduced cardiovascular end-points,41 highlighting potential therapeutic application, although no studies have specifically focused on diabetes. Other preclinical approaches targeting mitochondrial ROS include mitoTEMPO, a superoxide dismutase mimetic directed against mitochondria, which improves systolic/diastolic function in diabetic cardiomyopathy and reduces NADPH oxidase expression,42 although this has not been trialled in patients. Of potential ROS targets, Nox are perhaps most exciting given their specificity of signalling, although current preclinical inhibitors (eg, apocynin, VAS2870) remain non-selective for individual isoforms.…”

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

“…Compelling evidence demonstrates that the development of DCM is related to the induction of cardiac oxidative stress, as characterized by the production of ROS, leading to mitochondrial dysfunction, which in turn promotes cardiac oxidative stress [29,30]. Therefore, we investigated the effect of FGF21 deletion on the production of ROS and mitochondrial dysfunction in STZ/HFD-induced diabetic mice.…”