Poly(ADP-ribose) polymerase 1 deficiency increases nitric oxide production and attenuates aortic atherogenesis through downregulation of arginase II.

Abstract

Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12 weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity.

• Authors: Shu-Jian Wei, Lin Cheng, Er-Shun Liang, Qi Wang, Sheng-Nan Zhou, Hao Xu, Long-Hua Hui, Zhi-Ming Ge, Ming-Xiang Zhang
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 44 Issue 1 Pg. 114-122 (01 2017) ISSN: 1440-1681 [Electronic] Australia
• PMID: 27757983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 John Wiley & Sons Australia, Ltd.

Chemical References

• Cholesterol, Dietary
• Nitric Oxide
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Arg2 protein, mouse
• Arginase

Topics

• Animals
• Aorta (metabolism)
• Arginase (metabolism)
• Atherosclerosis (chemically induced, metabolism, prevention & control)
• Cells, Cultured
• Cholesterol, Dietary (adverse effects)
• Down-Regulation (physiology)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Nitric Oxide (biosynthesis)
• Poly (ADP-Ribose) Polymerase-1 (deficiency)