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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 30, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn179
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Na+/H+ exchanger is required for hyperglycemia-induced endothelial dysfunction via calcium-dependent calpain

Shuangxi Wang, Qisheng Peng1, Junhua Zhang2 and Liying Liu*

Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, Hunan, China
1 Current working address: College of Veterinary, Jilin University, Changchun 130062, China
2 Current working address: Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China

* To whom correspondence should be addressed: Professor Liying Liu, Department of Pharmacology, Pharmaceutical College, Central South University, 110 Xiang-Ya Road, Changsha, Hunan 410078, China. Tel: 86-731-4716249. Email: liyingliu2004{at}yahoo.com.cn

Aim: Recent studies have reported that the calcium-dependent protease calpain is involved in hyperglycemia-induced endothelial dysfunction and that the Na+/H+ exchanger (NHE) is responsible for an increase in the intracellular calcium (Ca2+i) concentration in diabetes. We hypothesized that activation of NHE mediates hyperglycemia-induced endothelial dysfunction via calcium-dependent calpain.

Methods and results: Exposure of human umbilical vein endothelial cells (HUVECs) to high glucose (HG, 30 mM D-glucose) time-dependently increased both the Ca2+i concentration and calpain activity. Chelation of free Ca2+i with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) abolished the HG-increased calpain activity. In addition, HG activated NHE in a time-dependent manner, but cariporide, an NHE inhibitor, blocked the HG-induced increase of NHE activity. Furthermore, cariporide or NHE siRNA attenuated the HG-induced increases of both Ca2+i concentration and calpain activity. All of these HG-induced effects in HUVECs, including decreased eNOS activity and NO production and increased dissociation of hsp90 from eNOS, were NHE or calpain reversible. In vivo experiments showed that cariporide treatment via inhibition of NHE activity significantly attenuated the hyperglycemia-induced impairment of acetylcholine-induced, endothelium-dependent relaxation in streptozotocin-injected diabetic rats.

Conclusion: Activation of NHE via calcium-dependent calpain contributes to hyperglycemia-induced endothelial dysfunction through dissociation of eNOS from hsp90.

KEYWORDS Na+/H+ exchanger; diabetes; endothelial function; calpain; eNOS

Time for primary review: 34 days


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