Poly(ADP-ribose)polymerase 1 inhibition protects against age-dependent endothelial dysfunction.
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.
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.|Department of Cardiology, Taian City Central Hospital, Shandong, China.
Guang-hao
GH
Zhang
Department of Anorectal surgery, Afliated Hospital of Jining Medical College, Jining, Shandong, China.
Min
M
Chao
The First Sanatorium of Jinan Military Region in Qingdao, Shandong, China.|Department of Cardiology, QiLu Hospital of Shandong University, Jinan, China.
Long-hua
LH
Hui
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Dong Ling
DL
Xu
Department of Cardiology, The Third Hospital, Jinan, China.
We-li
WL
Cai
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Jie
J
Zheng
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Min
M
Gao
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Ming-xiang
MX
Zhang
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Juan
J
Wang
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Qing-hua
QH
Lu
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013450:Sulfones; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D051057:Proto-Oncogene Proteins c-akt
PARP-1; aging; arginase-2; endothelial function; nitric oxide