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Poly(ADP-ribose)polymerase 1 inhibition protects against age-dependent endothelial dysfunction.
- Source :
-
Clinical and experimental pharmacology & physiology [Clin Exp Pharmacol Physiol] 2015 Dec; Vol. 42 (12), pp. 1266-74. - Publication Year :
- 2015
-
Abstract
- Age-related endothelial dysfunction is closely associated with the local production of reactive oxygen species (ROS) within and in the vicinity of the vascular endothelium. Oxidant-induced DNA damage can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), leading to endothelial dysfunction in various pathophysiological conditions. The present study aimed to investigate the role of PARP-1 in age-dependent changes in endothelial cell function and its underlying mechanism. Wild-type (WT) and PARP-1(-/-) mice were divided into young (2 months) and old (12 months) groups. Isolated aortic rings were suspended to record isometric tension to assess endothelial function. Nitric oxide (NO) production and content in plasma were detected by spectrophotometry. Superoxide (O2(-) production was detected by dihydroethidium. Expression of PARP-1, endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS), and arginase-2 (Arg2) was assessed by western blot analysis. Endothelium-dependent relaxation in response to acetylcholine was lost in old WT, but not PARP-1(-/-), mice. Endothelium-independent vasodilation was not impaired in aging mice. Production of O2(-) was greater in aging WT mice than young or aging PARP-1(-/-) mice. eNOS expression was not affected by aging in WT or PARP-1(-/-) mice, but p-eNOS expression decreased and iNOS and Arg2 levels were upregulated only in aging WT mice. In conclusion, PARP-1 inhibition may protect against age-dependent endothelial dysfunction, potentially by regulating NO bioavailability via iNOS. Inhibition of PARP-1 may help in vascular aging prevention.<br /> (© 2015 Wiley Publishing Asia Pty Ltd.)
- Subjects :
- Active Transport, Cell Nucleus drug effects
Aging drug effects
Aging genetics
Angiotensin II pharmacology
Animals
Cell Nucleus drug effects
Cell Nucleus metabolism
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Gene Expression Regulation, Enzymologic drug effects
Gene Expression Regulation, Enzymologic genetics
Humans
Male
Mice
NF-kappa B antagonists & inhibitors
NF-kappa B metabolism
Nitric Oxide metabolism
Nitric Oxide Synthase Type I metabolism
Nitric Oxide Synthase Type III metabolism
Nitriles pharmacology
Poly (ADP-Ribose) Polymerase-1 deficiency
Proto-Oncogene Proteins c-akt metabolism
Sulfones pharmacology
Superoxides metabolism
Aging metabolism
Endothelium, Vascular enzymology
Gene Deletion
Poly (ADP-Ribose) Polymerase-1 genetics
Poly (ADP-Ribose) Polymerase-1 metabolism
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1440-1681
- Volume :
- 42
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Clinical and experimental pharmacology & physiology
- Publication Type :
- Academic Journal
- Accession number :
- 26331430
- Full Text :
- https://doi.org/10.1111/1440-1681.12484