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Cardiovascular Research Advance Access first published online on June 30, 2008
This version [Corrected Proof] published online on July 21, 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 hyperglycaemia-induced endothelial dysfunction via calcium-dependent calpain

Shuangxi Wang, Qisheng Peng{dagger}, Junhua Zhang{ddagger} and Liying Liu*

Department of Pharmacology, Pharmaceutical College, Central South University, 110 Xiang-Ya Road, Changsha, Hunan 410078, China

* Corresponding author. Tel: +86 731 471 6249. E-mail address: liyingliu2004{at}yahoo.com.cn

Aims: Recent studies have reported that the calcium-dependent protease calpain is involved in hyperglycaemia-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 hyperglycaemia-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 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 in NHE activity. Furthermore, cariporide or NHE siRNA (small interfering ribonucleic acid) attenuated the HG-induced increases of both Ca2+i concentration and calpain activity. All of these HG-induced effects in HUVECs, including decreased endothelial nitric oxide synthase (eNOS) activity and NO (nitric oxide) production and increased dissociation of heat shock protein (hsp90) from eNOS, were NHE or calpain reversible. In vivo experiments showed that cariporide treatment via inhibition of NHE activity significantly attenuated the hyperglycaemia-induced impairment of acetylcholine-induced endothelium-dependent relaxation in streptozotocin-injected diabetic rats.

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

KEYWORDS Na+/H+ exchanger; Diabetes; Endothelial function; Calpain; eNOS

Time for primary review: 34 days

{dagger} Present address. College of Veterinary Medicine, Jilin University, Changchun 130062, China.

{ddagger} Present address. Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.


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