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Int J Cardiol. 2013 Sep 30;168(2):1017-22. doi: 10.1016/j.ijcard.2012.10.032. Epub 2012 Nov 17.

Endothelial progenitor cells in relation to endothelin-1 and endothelin receptor blockade: a randomized, controlled trial.

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Department of Medicine, Division of Cardiology, Karolinska Institutet, Stockholm, Sweden. Electronic address:



Endothelial progenitor cells (EPC) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis. Patients with both diabetes and vascular disease have low numbers of circulating EPC. The endothelium-derived peptide, endothelin-1 (ET-1), is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction. Therefore, we investigated the relation between EPC and plasma ET-1 and the effect of dual ET-1 receptor antagonist treatment.


In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual ETA/ETB receptor antagonist bosentan treatment (125mg bid; n=17) or placebo (n=19) for four weeks. Different EPC subpopulations were enumerated by flow cytometry using triple staining (CD34, CD133, KDR) at baseline at the end of treatment. Viability was assessed by 7AAD and Annexin-V-staining.


Baseline ET-1 levels correlated significantly with C-reactive protein levels. Patients with ET-1 levels above the median value had higher levels of CD34(+)CD133(+) and CD34(+)KDR(+) EPC. There was no difference in CD34(+) and CD34(+)CD133(+)KDR(+) cells, markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET-1 levels below or above the median. Four week treatment with bosentan did not change EPC levels.


Among patients with type 2 diabetes and vascular disease, high plasma levels of ET-1 are associated with higher number of EPC. The recruitment of EPC does not seem to be regulated via ET-1 receptor activation since treatment with a dual ET-1 receptor blocker did not affect circulating EPC numbers.


Bosentan; Diabetes; Endothelial progenitor cells; Endothelin-1; Vascular diseases

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