Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice

• Published in: Free radical biology & medicine Vol. 60; pp. 307 - 317
• Main Authors: Huynh, Karina, Kiriazis, Helen, Du, Xiao-Jun, Love, Jane E., Gray, Stephen P., Jandeleit-Dahm, Karin A., McMullen, Julie R., Ritchie, Rebecca H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2013
• Subjects: angiotensin-converting enzyme inhibitors; Animals; Apoptosis; Apoptosis - drug effects; blood lipids; blood pressure; Cardiomyocyte; cardiomyocytes; cardiomyopathy; citrates; Coenzyme Q10; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetic Cardiomyopathies - drug therapy; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - pathology; Diastolic function; echocardiography; Fibrosis; Free radicals; glycemic control; Humans; hyperglycemia; Hyperglycemia - complications; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hyperglycemia - pathology; Hypertrophy; Inflammation; insulin-dependent diabetes mellitus; interleukin-1beta; lipid peroxidation; Lipid Peroxidation - drug effects; Male; Mice; necrosis; Oxidative Stress; patients; reactive oxygen species; Reactive Oxygen Species - metabolism; streptozotocin; Superoxide; tumor necrosis factor-alpha; Ubiquinone - administration & dosage; Ubiquinone - analogs & derivatives; Up-Regulation; Ventricular Remodeling - drug effects; ANP; CoQ; LV; MDA; E:A; CTGF; HW; Diastolic function; DT; LVEDP; AoSBP; Coenzyme Q10; STZ; LVESD; Free radicals; H&E; Inflammation; Superoxide; ACE-I; LVEDD; Cardiomyocyte; Fibrosis; ROS; BCL2; TL; BAX; Diabetes; Apoptosis; Hypertrophy
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2013.02.021

Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left-ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated proinflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55mg/kg/day for 5 days), to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, the mice were allocated to coenzyme Q10 supplementation (10mg/kg/day), treatment with the angiotensin-converting-enzyme inhibitor (ACE-I) ramipril (3mg/kg/day), treatment with olive oil vehicle, or no treatment for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22phox, p47phox and superoxide production), LV uncoupling protein UCP3 expression, and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q10. Coenzyme Q10 substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure, and LV −dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis), and LV expression of proinflammatory mediators (tumor necrosis factor-α, with a similar trend for interleukin IL-1β). Coenzyme Q10's actions were independent of glycemic control, body mass, and blood pressure. Coenzyme Q10 compared favorably to improvements observed with ramipril. In summary, these data suggest that coenzyme Q10 effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q10 supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients. ► Targeting LV reactive oxygen species upregulation attenuates type 1 diabetic cardiomyopathy. ► Coenzyme Q10 blunted cardiac NADPH oxidase and oxidative stress. ► Cardiac remodeling, dysfunction, and inflammatory markers were similarly attenuated. ► Coenzyme Q10 effectively limits the cardiac complications of type 1 diabetes.