Diabetes induces pulmonary artery endothelial dysfunction by NADPH oxidase induction.
Recent data suggest that diabetes is a risk factor for pulmonary hypertension. The aim of the present study was to analyze whether diabetes induces endothelial dysfunction in pulmonary arteries and the mechanisms involved. Male Sprague-Dawley rats were randomly divided into a control (saline) and a diabetic group (70 mg/kg(-1) streptozotocin). After 6 wk, intrapulmonary arteries were mounted for isometric tension recording, and endothelial function was tested by the relaxant response to acetylcholine. Protein expression and localization were measured by Western blot and immunohistochemistry and superoxide production by dihydroethidium staining. Pulmonary arteries from diabetic rats showed impaired relaxant response to acetylcholine and reduced vasoconstrictor response to the nitric oxide (NO) synthase inhibitor L-NAME, whereas the response to nitroprusside and the expression of endothelial NO synthase remained unchanged. Endothelial dysfunction was reversed by addition of superoxide dismutase or the NADPH oxidase inhibitor apocynin. An increase in superoxide production and increased expression of the NADPH oxidase regulatory subunit p47(phox) were also found in pulmonary arteries from diabetic rats. In conclusion, the pulmonary circulation is a target for diabetes-induced endothelial dysfunction via enhanced NADPH oxidase-derived superoxide production.
Lopez-Lopez
Jose G
JG
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense Madrid, Madrid, Spain.
Moral-Sanz
Javier
J
Frazziano
Giovanna
G
Gomez-Villalobos
Maria J
MJ
Flores-Hernandez
Jorge
J
Monjaraz
Eduardo
E
Cogolludo
Angel
A
Perez-Vizcaino
Francisco
F
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D004727:Endothelium / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D019255:NADPH Oxidases / Q000096:biosynthesis*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D013481:Superoxides; D009569:Nitric Oxide; D019255:NADPH Oxidases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester