PT  - JOURNAL ARTICLE
AU  - Hwang, Hye Mi
AU  - Lee, Jeong Hyung
AU  - Min, Byung Sun
AU  - Jeon, Byeong Hwa
AU  - Hoe, Kwang Lae
AU  - Kim, Young Myeong
AU  - Ryoo, Sungwoo
TI  - A Novel Arginase Inhibitor Derived from <em>Scutellavia indica</em> Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet
AID  - 10.1124/jpet.115.224592
DP  - 2015 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 57--65
VI  - 355
IP  - 1
4099  - http://jpet.aspetjournals.org/content/355/1/57.short
4100  - http://jpet.aspetjournals.org/content/355/1/57.full
SO  - J Pharmacol Exp Ther2015 Oct 01; 355
AB  - 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)-5,2′,5′-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 TDF-mediated 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−/− 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.