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Cardiovascular Research Advance Access first published online on September 3, 2009
This version [Corrected Proof] published online on September 25, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp305
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

NF-{kappa}B-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes

Nithya Mariappan1, Carrie M. Elks1, Srinivas Sriramula1, Anuradha Guggilam1, Zhizhen Liu1,2, Olga Borkhsenious1 and Joseph Francis1,*

1 Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
2 Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China

* Corresponding author. Tel: +1 225 578 9752, Fax: +1 225 578 9895, Email: jfrancis{at}lsu.edu

Aims: Inflammatory molecules and their transcription factor, nuclear factor kappa-B (NF-{kappa}B), are thought to play important roles in diabetes-induced cardiac dysfunction. Here, we investigated the effects of pyrrolidine dithiocarbamate (PDTC), a NF-{kappa}B inhibitor, in diabetic mice.

Methods and 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-{kappa}B activity in db/db mice was associated with increased oxidative stress as demonstrated by increased ROS, superoxide, and peroxynitrite production, and increased NF-{kappa}B, 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.

Conclusion: This study demonstrates that NF-{kappa}B 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.

KEYWORDS Type II diabetes; NF-{kappa}B; Mitochondria; Oxidative stress; Free radicals

Time for primary review: 25 days


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