Restoration of the endothelial function in the aortic rings of apolipoprotein E deficient mice by pharmacological inhibition of the nuclear enzyme poly(ADP-ribose) polymerase.
Oxidant-mediated activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. The aim of the current study was to investigate whether activation of PARP contributes to the development of endothelial dysfunction in the apolipoprotein E (ApoE) deficient mice. We tested whether PARP inhibition prevents the development of endothelial dysfunction and whether it restores function in vessels with established endothelial dysfunction. ApoE deficient mice were kept on high-fat diet for 12 weeks with and without INO-1001 treatment. Chronic treatment with the PARP inhibitor INO-100 reduced the degree of the endothelial dysfunction (the ability of the vessel to relax to acetylcholine) in the thoracic aortae of ApoE deficient mice. In addition, in vitro incubation of vessels from ApoE deficient mice with established endothelial dysfunction with the PARP inhibitor acutely improved the ability of the rings to relax to acetylcholine. We conclude that the early atherosclerotic functional alterations that develop in the endothelium of the ApoE deficient mice are, at least in part, reversible, and are dependent on the activation of the nuclear enzyme PARP in the endothelial cells.
Benkö
Rita
R
Inotek Pharmaceuticals Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA. szabocsaba@aol.com
Pacher
Pál
P
Vaslin
Anne
A
Kollai
Márk
M
Szabó
Csaba
C
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000502:physiology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020127:Recovery of Function; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001057:Apolipoproteins E; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000109:Acetylcholine