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

doi:10.1093/cvr/cvn179

Cardiovascular Research Advance Access originally published online on June 30, 2008
Cardiovascular Research 2008 80(2):255-262; doi:10.1093/cvr/cvn179

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

Shuangxi Wang, Qisheng Peng, Junhua Zhang 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 proteasecalpain is involved in hyperglycaemia-induced endothelial dysfunctionand that the Na⁺/H⁺ exchanger (NHE) is responsible for an increasein the intracellular calcium (Ca²⁺_i) concentration in diabetes.We hypothesized that activation of NHE mediates hyperglycaemia-inducedendothelial 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 increasedboth the Ca²⁺_i concentration and calpain activity. Chelationof free Ca²⁺_i with 1,2-bis (2-aminophenoxy) ethane-N, N, N',N'-tetraaceticacid 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 ribonucleicacid) attenuated the HG-induced increases of both Ca²⁺_i concentrationand 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 dissociationof heat shock protein (hsp90) from eNOS, were NHE or calpainreversible. In vivo experiments showed that cariporide treatmentvia inhibition of NHE activity significantly attenuated thehyperglycaemia-induced impairment of acetylcholine-induced endothelium-dependentrelaxation in streptozotocin-injected diabetic rats.

Conclusion: Activation of NHE via calcium-dependent calpain contributesto hyperglycaemia-induced endothelial dysfunction through dissociationof hsp90 from eNOS.

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

Time for primary review: 34 days

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

Present address. Department of Anesthesiology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences,Beijing 100730, China.

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