title: 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.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.|Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Shu-Jian
authors.initials: SJ
authors.lastname: Wei
authors.affiliation: Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Er-Shun
authors.initials: ES
authors.lastname: Liang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Zhou
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.|The First Sanatorium of Jinan Military Region, Qingdao, Shandong, China.
authors.forename: Long-Hua
authors.initials: LH
authors.lastname: Hui
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Ge
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001119:Arginase / Q000378:metabolism*; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000009:adverse effects; D015536:Down-Regulation / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency*
chemical_list: D002791:Cholesterol, Dietary; D009569:Nitric Oxide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C481673:Arg2 protein, mouse; D001119:Arginase
keywords: arginase II; atherogenesis; nitric oxide; poly (ADP-ribose) polymerase 1