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-gamma agonist rosiglitazone.
Circulation
; 116(2): 163-73, 2007 Jul 10.
Article
em En
| MEDLINE
| ID: mdl-17592079
ABSTRACT
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-gamma agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals. METHODS ANDRESULTS:
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 p.o.) 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 p47(phox) 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-gamma agonism promotes vascular repair.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vasodilatadores
/
Endotélio Vascular
/
Estresse Oxidativo
/
Células Endoteliais
/
Tiazolidinedionas
/
PPAR gama
/
Diabetes Mellitus Tipo 2
/
Angiopatias Diabéticas
Tipo de estudo:
Clinical_trials
Limite:
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article