Protective Effects of PARP-1 Knockout on Dyslipidemia-Induced Autonomic and Vascular Dysfunction in ApoE−/− Mice: Effects on eNOS and Oxidative Stress
et al. (2009) Protective Effects of PARP-1 Knockout on Dyslipidemia-Induced Autonomic and Vascular
Dysfunction in ApoE2/2 Mice: Effects on eNOS and Oxidative Stress. PLoS ONE 4(10): e7430. doi:10.1371/journal.pone.0007430
Protective Effects of PARP-1 Knockout on Dyslipidemia- 2/2 Induced Autonomic and Vascular Dysfunction in ApoE Mice: Effects on eNOS and Oxidative Stress
Chetan P. Hans 0
Yumei Feng 0
Amarjit S. Naura 0
Mourad Zerfaoui 0
Bashir M. Rezk 0
Huijing Xia 0
Alan D. Kaye 0
Khalid Matrougui 0
Eric Lazartigues 0
A. Hamid Boulares 0
Marcelo Bonini, National Institutes of Health (NIH) / National Institute of Environmental Health Sciences (NIEHS), United States of America
0 1 Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center , New Orleans , Louisiana, United States of America, 2 Department of Anesthesiology Louisiana State University Health Sciences Center , New Orleans , Louisiana, United States of America, 3 Department of Physiology, Tulane University Medical Center , New Orleans, Louisiana , United States of America
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)2/2 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 ApoE2/2 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 dyslipidemiamediated 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.
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Funding: National Institutes of Health HL072889 and 1P20RR18766 (overall Principal Investigator, D. Kapusta) to A.H.B; American Heart Association Postdoctoral
fellowship to C.P.H (0825470E). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
Atherosclerosis, a major contributor to morbidity and mortality
in developed countries, is the underlying cause of a number of
cardiovascular diseases and is closely associated with dyslipidemia
[1,2]. Significant research has demonstrated that lipid-associated
disorders, such as atherosclerosis, are linked to alterations in
hemodynamic parameters, which may result in pathological
cardiovascular events [1,2,3]. Hypertension and dyslipidemia are
mechanistically linked and may act in synergy at the arterial wall
to enhance atherogenesis. The autonomic nervous system serves as
the main regulator of blood pressure and heart rate homeostasis, in
part, by modulation of the arterial baroreflex [4]. Indeed, reduced
spontaneous baroreflex sensitivity (SBRS) is associated with
impaired cardiac autonomic balance in hypertension, coronary
artery disease, and myocardial infarction [5,6]. In addition,
disruption in the balance between parasympathetic and
sympathetic tones can lead to cardiovascular dysfunction [6,7].
Endothelial dysfunction has been shown to be a reliable early
marker for atherosclerosis [8]. Nitric oxide (NO), a product of
endothelial NO synthase (eNOS), is released by the vascular
endothelium in response to various stimuli including
acethylcholine (Ach), and plays an important role in endothelium-dependent
vasodilation. Molecular mechanisms responsible for endothelial
dysfunction may include decreased expression of eNOS protein,
alterations in the membrane signaling pathway leading to eNOS
enzymatic activation (e.g., signaling-induced eNOS
phosphorylation), and decreased NO bioavailability through oxidants such as
superoxide (O2?2) [9,10]. Numerous studies have demonstrated
that hypercholesterolemia is as (...truncated)