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This article is part of the supplement: 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access Poster presentation

Endothelial GC-A can be a therapeutic target for metabolic syndrome

Takeshi Tokudome1*, Kentaro Otani2, Ichiro Kishimoto1, Yuanjie Mao1, Kazuwa Nakao3 and Kenji Kangawa4

Author Affiliations

1 Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

2 Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

3 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan

4 National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan

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BMC Pharmacology and Toxicology 2013, 14(Suppl 1):P73  doi:10.1186/2050-6511-14-S1-P73

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/2050-6511/14/S1/P73


Published:29 August 2013

© 2013 Tokudome et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

Atrial natriuretic peptide (ANP) has been used clinically for the treatment of heart failure patients in Japan, and also exhibits a variety of physiological effects through binding guanylyl cyclase-A (GC-A) receptor. We and other groups has been reported that GC-A is abundantly expressed in endothelial cells. In the present study, we explored the therapeutic potential of endothelial ANP/GC-A system for the treatment of metabolic syndrome.

Methods

We generated endothelial cell-specific GC-A transgenic mice using Tie2 promoter and enhancer (EC-GC-A-Tg), inducible endothelial cell-specific GC-A transgenic mice (Inducible EC-GC-A-Tg), and also endothelial cell-specific GC-A knockout mice (EC-GC-A-KO). In addition, we used eNOS transgenic mice (eNOS-Tg). For the evaluation of blood pressure, telemetry system and tail-cuff method were used. Insulin resistance was evaluated by intra-peritoneal glucose tolerance test (IPGTT) and intra-peritoneal insulin tolerance test (IPITT).

Results

The phenotypes of EC-GC-A-Tg were very unique. Systolic blood pressure in EC-GC-A-Tg was significantly lower compared with wild-type mice (WT). In addition, heat weight/body weight ratio and arterial elastance were smaller and lower in EC-GC-A-Tg compared with WT. Synchrotron radiation angiography showed decrease of basal vascular tone in EC-GC-A-Tg and increase in EC-GC-A-KO compared with in each control mice. Basal body weight of WT and EC-GC-A-Tg, flox mice and EC-GC-A-KO were comparable. However, after taking 8 weeks of high-fat diet, increase of body weight of EC-GC-A-Tg was significantly less than WT. On the other hand, EC-GC-A-KO showed more than increase of body weight. IPGTT and IPITT showed improvement of insulin tolerance in EC-GC-A-Tg, and worsen in EC-GC-A-KO compared with in each control mice. Interestingly, Inducible EC-GC-A-Tg showed less increase of body weight accompanied by aging. The body weight of eNOS-Tg was comparable with WT before and after taking 8 weeks of high-fat diet.

Conclusion

These data suggest that endothelial ANP/GC-A system can be a therapeutic target for metabolic syndrome.