Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice

Yoon, Jeongyeon; Park, Minjin; Lee, Jeong Hyung; Min, Byung Sun; Ryoo, Sungwoo

doi:10.1016/j.vph.2014.01.006

Cited by 25 publications

(16 citation statements)

References 42 publications

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“…Twenty male C57BL/6J wild-type (WT) and 20 male ApoE 2/2 mice (Daehan Biolink Co. Chungbuk, Korea) were obtained at 10 weeks of age and fed a normal diet (ND) and a high cholesterol diet (HCD, D12108C, Research Diet Inc.), respectively, for 8 weeks. Aortic rings were incubated with or without TDF at indicated concentrations for 18 hours as previously described (Yoon et al, 2014). The study was approved in accordance with the Guide for the Care and Use of Laboratory Animals (Institutional Review Board, Kangwon National University, South Korean).…”

Section: Methodsmentioning

confidence: 99%

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A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Hwang

Lee

Min

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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Elevated endothelial arginase activity decreases nitric oxide (NO) production by competing with the substrate L-arginine, previously reported, and reciprocally regulating endothelial nitric oxide synthase (eNOS) activity. Thus, arginase inhibitors may help treat vascular diseases associated with endothelial dysfunction. A screening of metabolites from medicinal plants revealed that (2S)-5,29,59-trihydroxy-7,8-dimethoxy flavanone (TDF) was a noncompetitive inhibitor of arginase. We investigated whether TDF reciprocally regulated endothelial NO production and its possible mechanism. TDF noncompetitively inhibited arginase I and II activity in a dose-dependent manner. TDF incubation decreased arginase activity and increased NO production in human umbilical vein endothelial cells and isolated mouse aortic vessels and reduced reactive oxygen species (ROS) generation in the endothelium of the latter. These TDFmediated effects were associated with increased eNOS phosphorylation and dimerization but not with changes in protein content. Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) were significantly increased in TDF-incubated aortic rings and attenuated by incubation with soluble guanylyl cyclase inhibitor. Phenylephrine-induced vasoconstrictor responses were markedly attenuated in TDF-treated vessels from wild-type mice. In atherogenic-prone ApoE 2/2 mice, TDF attenuated the high-cholesterol diet (HCD)-induced increase in arginase activity, which was accompanied by restoration of NO production and reduction of ROS generation. TDF incubation induced eNOS dimerization and phosphorylation at Ser1177. In addition, TDF improved Ach-dependent vasorelaxation responses and attenuated U46619-dependent contractile responses but did not change sodium nitroprusside-induced vasorelaxation or N-NAME-induced vasoconstriction. The findings suggest that TDF may help treat cardiovascular diseases by reducing pathophysiology derived from HCD-mediated endothelial dysfunction.

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Section: Methodsmentioning

confidence: 99%

“…NO was estimated by the nitrite/nitrate ratio (NOx), calculated using the Griess test to assess the conversion of nitrate to nitrite by nitrate reductase using a Nitric Oxide assay kit (Calbiochem) as previously described (Yoon et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Hwang

Lee

Min

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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“…Obacunone (OBA), a highly oxygenated triterpenoid (limonoid), is commonly found in citrus and other plants of the Rutaceae family (eg, Phellodendron chinense, Dictamnus dasycarpus , and Euodia rutaecarpa ). Similar to other citrus limonoids, OBA exhibits various promising biological and pharmacological activities, including anti‐oxidative, anti‐obesity, anti‐hyperglycemic, neuro‐ and endothelial‐protective, antimalarial, and anti‐tumor . However, the effect and mechanism of OBA on inflammation remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Obacunone causes sustained expression of MKP‐1 thus inactivating p38 MAPK to suppress pro‐inflammatory mediators through intracellular MIF

Gao

Hou

Liu

et al. 2017

J of Cellular Biochemistry

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Obacunone (OBA) is a highly oxygenated triterpenoid with various pharmacological activities. In this study, we explored its anti-inflammatory effect and underlying mechanisms in LPS-activated macrophages. Our data showed that OBA potently decreased pro-inflammatory mediators (eg, NO, IL-6, IL-1β, and MCP-1) at the transcriptional and translational levels without cytotoxicity. A mechanism study showed that OBA significantly suppressed p38-mediated AP-1 signaling by stabilizing the mRNA of mitogen-activated protein kinase phosphatase 1 (MKP-1), thus prolonging the expression time of the MKP-1 protein. Next, we used computational target-fishing technology to predict the possible target of OBA. Only one potential target, macrophage migration inhibitory factor (MIF), was presented.Experimentally, the interaction between OBA and MIF was also confirmed. By using an anti-mouse MIF antibody, extracellular MIF (exMIF) was neutralized. Our results showed that autocrine MIF had slight influence on the pro-inflammatory mediator production. Correspondingly, the anti-inflammatory activity of OBA was also not affected. Accordingly, we knocked down the MIF gene in RAW 264.7 cells and obtained stable MIF deficient cells MIF(−), in which the effects of OBA on p38 phosphorylation, AP-1 activation, and pro-inflammatory mediator production in response to LPS nearly disappeared. In contrast to MIF(+) cells, the MKP-1 protein expression time of the MIF(−) cells was markedly prolonged. We conclude that OBA exerts its anti-inflammatory effect by targeting intracellular MIF (inMIF) inhibition to regulate the MKP-1/p38/AP-1 pathway. Our findings also provide a chain of evidence that the inhibition of inMIF, rather than exMIF, may become a novel target for inflammation.

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“…Obacunone is a small molecular compound derived from citrus fruits with a higher content in seeds. Published studies indicate that obacunone can inhibit cancer proliferation and has some therapeutic effects on cardiovascular diseases (Poulose et al, 2006; Yoon et al, 2014). As expected, the protein levels of Nrf2 were increased in various cell types after obacunone treatment, while Keap1 levels remained constant in MDA-MB-231 cells (Fig.…”

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confidence: 99%

Obacunone activates the Nrf2-dependent antioxidant responses

Chen

Xie

et al. 2016

Protein Cell

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Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice

Cited by 25 publications

References 42 publications

A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Obacunone causes sustained expression of MKP‐1 thus inactivating p38 MAPK to suppress pro‐inflammatory mediators through intracellular MIF

Obacunone activates the Nrf2-dependent antioxidant responses

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