Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation.
Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.
Garcia Soriano F
Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, Massachusetts 01915, and Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, 185 University Heights, Newark, NJ 01703, USA.
Virág
L
L
Jagtap
P
P
Szabó
E
E
Mabley
J G
JG
Liaudet
L
L
Marton
A
A
Hoyt
D G
DG
Murthy
K G
KG
Salzman
A L
AL
Southan
G J
GJ
Szabó
C
C
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology*; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D016328:NF-kappa B; D011065:Poly(ADP-ribose) Polymerases; D005947:Glucose