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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103480-07
Application #
8730202
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Soni, Kruti S; Lei, Fan; Desale, Swapnil S et al. (2017) Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. J Control Release 264:276-287
Karuturi, Bala V K; Tallapaka, Shailendra B; Yeapuri, Pravin et al. (2017) Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diamet Mol Pharm 14:1469-1481
Fan, Wei; Zhang, Wenting; Jia, Yinnong et al. (2017) Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers. Mol Pharm 14:1405-1417
Chen, Shixuan; Ge, Liangpeng; Mueller, Aubrey et al. (2017) Twisting electrospun nanofiber fine strips into functional sutures for sustained co-delivery of gentamicin and silver. Nanomedicine 13:1435-1445
Chen, Shixuan; Ge, Liangpeng; Gombart, Adrian F et al. (2017) Nanofiber-based sutures induce endogenous antimicrobial peptide. Nanomedicine (Lond) 12:2597-2609
Jiang, Jiang; Chen, Shixuan; Wang, Hongjun et al. (2017) CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. Acta Biomater :
Shrishrimal, Shashank; Kosmacek, Elizabeth A; Chatterjee, Arpita et al. (2017) The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. Antioxidants (Basel) 6:
Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830
Smolsky, Joseph; Kaur, Sukhwinder; Hayashi, Chihiro et al. (2017) Surface-Enhanced Raman Scattering-Based Immunoassay Technologies for Detection of Disease Biomarkers. Biosensors (Basel) 7:
Lakshmanan, Imayavaramban; Salfity, Shereen; Seshacharyulu, Parthasarathy et al. (2017) MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53. Clin Cancer Res 23:3906-3917

Showing the most recent 10 out of 74 publications