Protective effects of PARP-1 knockout on dyslipidemia-induced autonomic and vascular dysfunction in ApoE mice: effects on eNOS and oxidative stress.
The aims of this study were to investigate the role of poly(ADP-ribose) polymerase (PARP)-1 in dyslipidemia-associated vascular dysfunction as well as autonomic nervous system dysregulation. Apolipoprotein (ApoE)(-/-) mice fed a high-fat diet were used as a model of atherosclerosis. Vascular and autonomic functions were measured in conscious mice using telemetry. The study revealed that PARP-1 plays an important role in dyslipidemia-associated vascular and autonomic dysfunction. Inhibition of this enzyme by gene knockout partially restored baroreflex sensitivity in ApoE(-/-) mice without affecting baseline heart-rate and arterial pressure, and also improved heart-rate responses following selective blockade of the autonomic nervous system. The protective effect of PARP-1 gene deletion against dyslipidemia-induced endothelial dysfunction was associated with preservation of eNOS activity. Dyslipidemia induced PARP-1 activation was accompanied by oxidative tissue damage, as evidenced by increased expression of iNOS and subsequent protein nitration. PARP-1 gene deletion reversed these effects, suggesting that PARP-1 may contribute to vascular and autonomic pathologies by promoting oxidative tissue injury. Further, inhibition of this oxidative damage may account for protective effects of PARP-1 gene deletion on vascular and autonomic functions. This study demonstrates that PARP-1 participates in dyslipidemia-mediated dysregulation of the autonomic nervous system and that PARP-1 gene deletion normalizes autonomic and vascular dysfunctions. Maintenance of eNOS activity may be associated with the protective effect of PARP-1 gene deletion against dyslipidemia-induced endothelial dysfunction.
Hans
Chetan P
CP
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
Feng
Yumei
Y
Naura
Amarjit S
AS
Zerfaoui
Mourad
M
Rezk
Bashir M
BM
Xia
Huijing
H
Kaye
Alan D
AD
Matrougui
Khalid
K
Lazartigues
Eric
E
Boulares
A Hamid
AH
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D004041:Dietary Fats; D050171:Dyslipidemias / Q000235:genetics*; D017353:Gene Deletion; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*
D001057:Apolipoproteins E; D004041:Dietary Fats; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011065:Poly(ADP-ribose) Polymerases