Although oxidative stress is a prevalent condition in obesity, the role of oxidative stress initiated by superoxide in modulating adipose tissue (AT)-specific inflammation in obesity remains unclear. Moreover, the potential role of antioxidants in modulating the inflammatory state of obese AT and subsequent development of systemic hypertension is unknown. Our preliminary data show that pretreatment of human aortic endothelial cells with nanoformulated copper/zinc superoxide dismutase (nanoSOD) but not native or PEG-SOD reduces linoleic acid-induced superoxide production. Our in vivo data show that nanoSOD reduces superoxide-mediated oxidative stress in obese AT as evident from decreased nitrotyrosine content in the AT stromal vascular fraction. Because oxidative stress is often associated with inflammation and because AT-specific inflammation mediates the pathological consequence of obesity, we hypothesize that reduction of AT superoxide using nanoSOD will lead to reduced AT-inflammation which, in turn, will lead to reduced systemic hypertension in obesity. The studies proposed in this application will take physiological, pharmacological, and molecular approaches to investigate how reduction of superoxide using nanoSOD in obesity will impact the development of systemic hypertension. Because endothelial cell oxidative stress is an underlying event linking obesity and hypertension, we will determine the role of nanoSOD in delivering active SOD to endothelial cells and in scavenging free fatty acid-induced superoxide in Specific Aim 1.
In Specific Aim 2, we will determine the biodistribution of SOD delivered as nanoSOD in a model of diet induced obesity. Wild type mice will be fed a high fat diet (45% fat) for 12 wk and injected with 1251-labelled nanoSOD. SPECT imaging will be carried out to determine the biodistribution of SOD in tissues including visceral AT, liver, and spleen.
In Specific Aim 3, we will determine the toxicity of nanoSOD in a model of diet-induced obesity. We will also study the effectiveness of nanoSOD in scavenging superoxide from AT and in reducing systemic hypertension in obesity. Briefly, after 12 wk on high fat diet, the mice will receive the nanozymes for 2 wk. At the end of 14 wk, we will analyze AT superoxide, AT-inflammation and systemic hypertension. The findings will be relevant to determining the therapeutic potential of nanoformulated antioxidant enzymes in treating chronic cardiovascular risk factors in obesity.

Public Health Relevance

Obesity and its complications remain the major healthcare problems in the US and worldwide. At present no pharmacotherapy is available to efficiently manage the metabolic disorders associated with obesity. Our studies will determine the effect of nanoformulated antioxidant enzymes, in particular, copper/zinc superoxide dismutase, in modulating adipose tissue oxidative stress and systemic hypertension in obesity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1-TWD-Y (C2))
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University of Nebraska Medical Center
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