Abstract
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.
Highlights
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]
In order to verify that poly(ADP-ribose) polymerase (PARP)-1 gene deletion protects against plaque formation in a murine model of atherosclerosis, aortas were collected from ApoE2/2 or Double Knockout (DKO) mice after a 16-week regimen with regular (RD) or high-fat (HF) diet
PARP-1 gene deletion markedly lowered the incidence of these lesions along the aorta in high-fat diet (HF) fed mice, but this decrease was most prominent in the abdominal region (Figure 1A, B)
Summary
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]. Reduced spontaneous baroreflex sensitivity (SBRS) is associated with impaired cardiac autonomic balance in hypertension, coronary artery disease, and myocardial infarction [5,6]. Disruption in the balance between parasympathetic and sympathetic tones can lead to cardiovascular dysfunction [6,7]
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