NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes.
OBJECTIVE
Inflammatory molecules and their transcription factor, nuclear factor kappa-B (NF-kappaB), are thought to play important roles in diabetes-induced cardiac dysfunction. Here, we investigated the effects of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, in diabetic mice.


RESULTS
Obese db/db mice and heterozygous lean mice (n = 8) were allowed free access to drinking water (control) or water containing PDTC (100 mg/kg) for 20 weeks. Left ventricular (LV) function was measured using echocardiography at baseline and at study end. Mice were sacrificed and LV removed for gene expression, biochemical, immunofluorescence, and mitochondrial assays. LV and mitochondrial reactive oxygen species (ROS), superoxide and peroxynitrite were measured using electron spin resonance spectroscopy. Enhanced NF-kappaB activity in db/db mice was associated with increased oxidative stress as demonstrated by increased ROS, superoxide, and peroxynitrite production, and increased NF-kappaB, gp91phox, and Nox1 expression; PDTC ameliorated these effects. Mitochondrial free radical production and structural damage were higher in the db/db group than in the control, db/db PDTC, and PDTC-treated heterozygous animal groups.


CONCLUSIONS
This study demonstrates that NF-kappaB blockade with PDTC mitigates oxidative stress and improves mitochondrial structural integrity directly, through down-regulation of increased oxygen-free radicals, thereby increasing ATP synthesis and thus restoring cardiac function in type II diabetes.
Mariappan
Nithya
N
Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
Elks
Carrie M
CM
Sriramula
Srinivas
S
Guggilam
Anuradha
A
Liu
Zhizhen
Z
Borkhsenious
Olga
O
Francis
Joseph
J
D000818:Animals; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004452:Echocardiography; D014450:Electron Transport Complex III / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D006321:Heart / Q000503:physiopathology*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009929:Organ Size; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015850:Interleukin-6; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D014450:Electron Transport Complex III; D005978:Glutathione