Targeting the increase in oxidative stress in diabetic cardiomyopathy using coenzyme Q10
Creators: name: Huynh, Karina
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Diabetes is one of the fastest growing chronic diseases of the 21st century. Diabetic patients are at increased risk of developing heart failure. Diabetic cardiomyopathy, characterized by early diastolic dysfunction and adverse morphological changes, develops independently of macrovascular and microvascular complications. The development of these changes are often attributed to increased oxidative stress, resulting from elevated reactive oxygen species (ROS) production and diminished antioxidant defences. Supplementation with the potent endogenous antioxidant coenzyme Q10 has been shown to be beneficial in improving cardiac function and reducing left ventricular (LV) hypertrophy outside of diabetes; its benefit in protecting the diabetic heart remains unknown. The first aim of the project was to determine the efficacy of coenzyme Q10 supplementation in protecting the heart from type 2 diabetes-induced damage, using the spontaneous db/db mouse model (obese and hypertensive). Mice were treated with coenzyme Q10, or with the angiotensin-converting enzyme inhibitor (ACE-I) ramipril daily for 10 weeks. Untreated db/db mice exhibited significant diastolic dysfunction in vivo, as well as cardiomyocyte hypertrophy, cardiac fibrosis and apoptosis. These adverse cardiac changes were accompanied by a significant upregulation in systemic lipid peroxidation and cardiac superoxide (•O2-) generation, with concomitant modest hypertension. Supplementation with coenzyme Q10 administration significantly attenuated diastolic dysfunction and was associated with reduced markers of hypertrophy, fibrosis and apoptosis in diabetic mice. Interestingly, coenzyme Q10 treatment in diabetic animals also tended to modestly improve glycemic control and lower blood pressure in diabetic animals. The efficacy of coenzyme Q10 and ramipril were comparable in this model. The second aim of the project was to determine the efficacy of coenzyme Q10 in protecting the non-obese, non-hypertensive type 1 diabetic heart from diabetes-induced damage. Insulin-deficient streptozotocin (STZ) mice were treated with either coenzyme Q10 or ramipril. As evident in db/db mice, untreated STZ type 1 diabetic mice exhibited diastolic dysfunction, cardiomyocyte hypertrophy, elevated cardiac collagen deposition and enhanced cardiomyocyte apoptosis. Markers of oxidative stress, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression (Nox2, p22phox, p47phox), 3-nitrotyrosine (3-NT) protein levels, NADPH-driven •O2- generation and systemic lipid peroxidation were all upregulated in untreated STZ mice. These mice also exhibited increased expression of pro-inflammatory markers tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β). Coenzyme Q10 attenuated all the adverse functional and structural changes in the diabetic heart, as well as reducing all markers of oxidative stress and inflammation. We have evidence that increased phosphoinositide 3-kinase(p110α) [PI3K(p110α)] signaling is protective (and diminished PI3K(p110α) signaling, detrimental) to the diabetic heart, and that this may be linked to PI3K(p110α) negative regulation of ROS generation. Hence, the third aim of the project was to determine whether coenzyme Q10 protects the diabetic dnPI3K heart from damage. Diabetic dnPI3K untreated mice exhibited reduced diastolic function and evidence of adverse cardiac remodeling, as previously observed. Coenzyme Q10 treatment of diabetic dnPI3K mice significantly attenuated diastolic function and the adverse changes in cardiac morphology. Interestingly, NADPH-driven •O2- generation was exacerbated in dnPI3K diabetic mice compared to non-transgenic (Ntg) diabetic mice. Coenzyme Q10 supplementation also reduced LV •O2- generation and diminished systemic lipid peroxidation in treated dnPI3K diabetic animals as part of its cardioprotection. In summary, this study highlighted the characteristic features of the type 1 and type 2 diabetic heart, which includes early diastolic dysfunction, and morphological changes including cardiomyocyte hypertrophy, cardiac fibrosis and enhanced apoptosis. This study showed for the first time that coenzyme Q10 was able to attenuate diastolic dysfunction and structural remodeling in the diabetic heart, likely via reduced LV •O2- generation and lipid peroxidation. Coenzyme Q10 was also effective in protecting the hearts of diabetic dnPI3K transgenic mice (in spite of exacerbated ROS levels). As coenzyme Q10 was at least as effective as ramipril in protecting the hearts of diabetic mice against damage, coenzyme Q10 may be a possible alternative or adjunct therapy to ACE-Is for the treatment of diabetic cardiomyopathy in the clinical setting.