Ferdinand Hermann Bahlmann

Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

Background—Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI. Methods and Results—Wild-type (WT) and eNO synthase (eNOS)−/− mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS−/− mice. LV dysfunction and interstitial fibrosis were markedly attenuated by Ator in WT mice, whereas no effect was observed in eNOS−/− mice after MI. Importantly, Ator significantly increased the survival rate during 4 weeks after MI in WT mice (Ator versus V, 80% versus 46%; P<0.01, n=75) but not in eNOS−/− mice (43% versus 48%; NS, n=42). Conclusions—These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.

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

Background— Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor-&ggr; agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals. Methods and Results— In vivo reendothelialization capacity of EPCs from diabetic patients (n=30) and healthy subjects (n=10) was examined in a nude mouse carotid injury model. Superoxide and NO production of EPCs was determined by electron spin resonance spectroscopy. Thirty patients with diabetes mellitus were randomized to 2 weeks of rosiglitazone (4 mg BID PO) or placebo treatment. In vivo reendothelialization capacity of EPCs derived from diabetic subjects was severely reduced compared with EPCs from healthy subjects (reendothelialized area: 8±3% versus 37±10%; P<0.001). EPCs from diabetic individuals had a substantially increased superoxide production and impaired NO bioavailability. Small-interfering RNA silencing of NAD(P)H oxidase subunit p47phox reduced superoxide production and restored NO bioavailability and in vivo reendothelialization capacity of EPCs from diabetic patients. Importantly, rosiglitazone therapy normalized NAD(P)H oxidase activity, restored NO bioavailability, and improved in vivo reendothelialization capacity of EPCs from diabetic patients (reendothelialized area: placebo versus rosiglitazone, 8±1% versus 38±5%; P<0.001). Conclusions— In vivo reendothelialization capacity of EPCs derived from individuals with diabetes mellitus is severely impaired at least partially as a result of increased NAD(P)H oxidase–dependent superoxide production and subsequently reduced NO bioavailability. Rosiglitazone therapy reduces NAD(P)H oxidase activity and improves reendothelialization capacity of EPCs from diabetic individuals, representing a potential novel mechanism whereby peroxisome proliferator-activated receptor-&ggr; agonism promotes vascular repair.

Anemia and Progression of Chronic Kidney Disease

Tubulointerstitial fibrosis that results from renal tissue hypoxia is thought to be a key element of progressive chronic kidney diseases (CKD). Findings from epidemiological studies suggest that anemia in patients with CKD due to inadequate erythropoietin (EPO) secretion may contribute to progression. However, results of prospective controlled studies that evaluated the effect of recombinant human erythropoietin (rHuEPO) on the course of CKD were inconsistent. Nevertheless, slowing CKD progression with rHuEPO (and correction of anemia) may be achieved with a better understanding of the processes involved in the damage caused by renal tissue hypoxia.

Response to Letter 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”

We thank Thum and colleagues for their letter about our article.1 We agree that it is important to gain a better understanding of mechanisms leading to impaired in vitro and in vivo function of endothelial progenitor cells (EPCs) derived from patients with diabetes. This is not only important for a better understanding of the pathophysiology of the disease, but is also a prerequisite to optimize autologous progenitor cell-based therapeutic approaches. In both studies, an increased superoxide production of EPCs derived from diabetic patients has been observed that was suggested to contribute importantly to impaired in vitro and in vivo function.1,2 Whereas in our study, we focused on the oxidative enzyme system NAD(P)H oxidase as a …