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Cardiovasc Res. 2008 Nov 1;80(2):255-62. doi: 10.1093/cvr/cvn179. Epub 2008 Jun 30.

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

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  • 1Department of Pharmacology, Pharmaceutical College, Central South University, 110 Xiang-Ya Road, Changsha, Hunan 410078, China.



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 (Ca(2+)(i)) concentration in diabetes. We hypothesized that activation of NHE mediates hyperglycaemia-induced endothelial dysfunction via calcium-dependent calpain.


Exposure of human umbilical vein endothelial cells (HUVECs) to high glucose (HG, 30 mM d-glucose) time dependently increased both the Ca(2+)(i) concentration and calpain activity. Chelation of free Ca(2+)(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 Ca(2+)(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.


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

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