A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet.
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.
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea.
Hye Mi
HM
Hwang
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea.
Jeong Hyung
JH
Lee
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea.
Byung Sun
BS
Min
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea.
Byeong Hwa
BH
Jeon
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea.
Kwang Lae
KL
Hoe
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea.
Young Myeong
YM
Kim
Departments of Biological Sciences (H.M.H., S.R.) and Biochemistry (J.H.L.), College of Natural Sciences, and Departments of Molecular and Cellular Biochemistry (Y.M.K.), School of Medicine, Kangwon National University, Chuncheon, Gangwon-do; College of Pharmacy, Catholic University, Daegu (B.S.M.); Infectious Signaling Network Research Center, Department of Physiology, School of Medicine, (B.H.J.) and Department of New Drug Discovery and Development (K.L.H.), Chungnam National University, Daejeon, South Korea ryoosw08@kangwon.ac.kr.
Sungwoo
S
Ryoo
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001119:Arginase / Q000037:antagonists & inhibitors*; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D044950:Flavanones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D017353:Gene Deletion; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000432:Methanol / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D017382:Reactive Oxygen Species / Q000378:metabolism; D031363:Scutellaria / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D044950:Flavanones; D017382:Reactive Oxygen Species; C094747:dioclein; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C544448:Arg1 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase; D000432:Methanol