Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells

Lu, Chang-Wu; Guo, Zheng; Feng, Mei; Wu, Zhong-Zu; He, Zhi-Min; Xiong, Yan

doi:10.1016/j.atherosclerosis.2009.08.035

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Volume 209, Issue 1 , Pages 66-73, March 2010

Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells

Chang-Wu Lu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, 110# Xiang-ya Road, Changsha 410078, Hunan, PR China
Zheng Guo
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, 110# Xiang-ya Road, Changsha 410078, Hunan, PR China
Mei Feng
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, 110# Xiang-ya Road, Changsha 410078, Hunan, PR China
Zhong-Zu Wu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, 110# Xiang-ya Road, Changsha 410078, Hunan, PR China
Zhi-Min He
- Cancer Research Institute, Central South University, Changsha 410078, Hunan, PR China
Yan Xiong
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, 110# Xiang-ya Road, Changsha 410078, Hunan, PR China
- Corresponding author. Tel.: +86 731 82355080; fax: +86 731 82355041.

Received 12 October 2008; received in revised form 3 August 2009; accepted 17 August 2009.

Abstract

Objectives

Elevated level of asymmetric dimethylarginine (ADMA) is an independent risk factor for endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) is the key enzyme responsible for the degradation of endogenous ADMA. The purposes of this study were to determine whether suppressed DDAH2 expression would implicate in endothelial dysfunction associated with diabetes mellitus and further to investigate whether adenovirus-mediated DDAH2 gene overexpression could improve the hyperglycemia-induced endothelial dysfunction.

Methods

Diabetic model was induced by intraperitoneal injection of streptozotocin to male Sprague–Dawley rats. Recombinant adenoviral vector encoding human DDAH2 gene driven by a cytomegalovirus promoter was constructed to overexpress hDDAH2 gene in isolated rat aortas and endothelial cells. Changes in DDHA/ADMA/nitric oxide (NO) pathway in diabetic rats and high glucose-treated endothelial cells were examined.

Results

DDAH2 expression was distinctly suppressed, which was accompanied by inhibited DDAH activity and impaired endothelium-dependent relaxation in aortas, and elevated ADMA concentrations in serum of diabetic rats compared to control rats. Suppressions of DDAH2 expression and DDAH activity, accumulation of ADMA, and inhibition of NO synthesis were observed in high glucose-treated endothelial cells. DDAH2 overexpression not only improved endothelial dysfunction in diabetic aortas but also attenuated hyperglycemia-induced changes in DDAH/ADMA//NO pathway in endothelial cells.

Conclusion

These results indicate that suppression of DDAH2 expression contributes to hyperglycemia-induced endothelial dysfunction, which can be improved by DDAH2 overexpression. This study suggests that targeted modulation of DDAH2 gene in vascular endothelium may be a novel approach for the treatment of endothelial dysfunction in diabetes mellitus.

Keywords: Asymmetric dimethylarginine, Diabetes mellitus, Dimethylarginine dimethylaminohydrolase, Endothelial dysfunction, Gene transferring