Letter by Thum et al Regarding Article, “Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus: Restoration by the Peroxisome Proliferator- Activated Receptor-γ Agonist Rosiglitazone”
To the Editor:
We read with interest the recent article by Sorrentino et al1 regarding the improvement of endothelial progenitor cell (EPC) function in patients with type 2 diabetes mellitus by the peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone. Importantly, pharmacotherapy in diabetic patients was shown to result in an improved reendothelialization capacity of EPCs. The authors concluded that PPAR-γ–mediated repression of NADPH oxidase activity resulted in improved NO bioavailability in EPCs, which led to improved function.
We recently have shown involvement of endothelial nitric oxide synthase (eNOS) uncoupling and diminished tetrahydrobiopterin levels in EPC dysfunction in diabetic patients.2 An initial increase in NADPH oxidase activity may lead to oxidation of intracellular tetrahydrobiopterin levels in EPCs of diabetic patients, which in turn fosters eNOS uncoupling with a subsequent additional rise in reactive oxygen species (ROS) production. In line with this hypothesis, we found synergistic beneficial effects on ROS production and EPC function when both NADPH oxidase and eNOS were inhibited, although eNOS uncoupling played the dominant role in terms of ROS production.2 Differences in the investigated patient populations are a potential explanation for the partial discrepancy in the findings of Sorrentino et al.1 Sorrentino et al investigated patients with type 2 diabetes mellitus who had only slightly increased glycosylated hemoglobin levels (6.6±2.2%) without presentation of potential underlying antidiabetic treatments such as insulin, whereas we investigated EPCs from untreated diabetic patients with a high glycosylated hemoglobin level of 8.8±0.6%. Activation of NADPH oxidase likely occurs early in diabetes and/or in mild diabetic forms,1 whereas eNOS uncoupling with an even stronger subsequent production of ROS predominantly exists in advanced diabetes.2
Although the underlying molecular mechanisms are not entirely clear, we agree with the authors that a balance of NO and/or ROS within EPCs largely determines their functional behavior.1–3 After years of mainly descriptive research, investigators have begun in-depth mechanistic analyses to decipher the molecular causes of EPC dysfunction. These data will provide keys for the development of novel therapies, such as PPAR-γ agonism, for prevention and treatment of various cardiovascular diseases.
Sorrentino SA, Bahlmann FH, Besler C, Muller M, Schulz S, Kirchhoff N, Doerries C, Horváth T, Limbourg A, Limbourg F, Fliser D, Haller H, Drexler H, Landmesser U. Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone. Circulation. 2007; 116: 163–173.
Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007; 56: 666–674.
Thum T, Hoeber S, Froese S, Klink I, Stichtenoth DO, Galuppo P, Jakob M, Tsikas D, Anker SD, Poole-Wilson PA, Borlak J, Ertl G, Bauersachs J. Age-dependent impairment of endothelial progenitor cells is corrected by growth hormone mediated increase of insulin-like growth factor-1. Circ Res. 2007; 100: 434–443.