Syringaresinol causes vasorelaxation by elevating nitric oxide production through the phosphorylation and dimerization of endothelial nitric oxide synthase

Byung Hee Chung, Sookon Kim, Jong Dai Kim, Jung Joon Lee, Yi Yong Baek, Dooil Jeoung, Hansoo Lee, Jongseon Choe, Kwon Soo Ha, Moo Ho Won, Young Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in vascular functions, including vasorelaxation. We here investigated the pharmacological effect of the natural product syringaresinol on vascular relaxation and eNOS-mediated NO production as well as its underlying biochemical mechanism in endothelial cells. Treatment of aortic rings from wild type, but not eNOS -/- mice, with syringaresinol induced endothelium-dependent relaxation, which was abolished by addition of the NOS inhibitor N G -monomethyl-L-arginine. Treatment of human endothelial cells and mouse aortic rings with syringaresinol increased NO production, which was correlated with eNOS phosphorylation via the activation of Akt and AMP kinase (AMPK) as well as elevation of intracellular Ca 2+ levels. A phospholipase C (PLC) inhibitor blocked the increases in intracellular Ca 2+ levels, AMPK-dependent eNOS phosphorylation, and NO production, but not Akt activation, in syringaresinol- treated endothelial cells. Syringaresinol-induced AMPK activation was inhibited by co-treatment with PLC inhibitor, Ca 2+ chelator, calmodulin antagonist, and CaMKKβ siRNA. This compound also increased eNOS dimerization, which was inhibited by a PLC inhibitor and a Ca 2+ -chelator. The chemicals that inhibit eNOS phosphorylation and dimerization attenuated vasorelaxation and cGMP production. These results suggest that syringaresinol induces vasorelaxation by enhancing NO production in endothelial cells via two distinct mechanisms, phosphatidylinositol 3-kinase/Akt- and PLC/Ca 2+ /CaMKKβ-dependent eNOS phosphorylation and Ca 2+ -dependent eNOS dimerization.

Original languageEnglish
Pages (from-to)191-201
Number of pages11
JournalExperimental and Molecular Medicine
Volume44
Issue number3
DOIs
Publication statusPublished - 2012 Jan 1

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Phosphorylation
Dimerization
Nitric Oxide Synthase Type III
Vasodilation
Nitric Oxide Synthase
Nitric Oxide
Endothelial cells
Type C Phospholipases
Adenylate Kinase
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Endothelial Cells
Chemical activation
Chelating Agents
Blood Vessels
Phosphatidylinositol 3-Kinase
syringaresinol
Calmodulin
Biological Products
Small Interfering RNA
Endothelium

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Chung, Byung Hee ; Kim, Sookon ; Kim, Jong Dai ; Lee, Jung Joon ; Baek, Yi Yong ; Jeoung, Dooil ; Lee, Hansoo ; Choe, Jongseon ; Ha, Kwon Soo ; Won, Moo Ho ; Kwon, Young Guen ; Kim, Young Myeong. / Syringaresinol causes vasorelaxation by elevating nitric oxide production through the phosphorylation and dimerization of endothelial nitric oxide synthase. In: Experimental and Molecular Medicine. 2012 ; Vol. 44, No. 3. pp. 191-201.
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Syringaresinol causes vasorelaxation by elevating nitric oxide production through the phosphorylation and dimerization of endothelial nitric oxide synthase. / Chung, Byung Hee; Kim, Sookon; Kim, Jong Dai; Lee, Jung Joon; Baek, Yi Yong; Jeoung, Dooil; Lee, Hansoo; Choe, Jongseon; Ha, Kwon Soo; Won, Moo Ho; Kwon, Young Guen; Kim, Young Myeong.

In: Experimental and Molecular Medicine, Vol. 44, No. 3, 01.01.2012, p. 191-201.

Research output: Contribution to journalArticle

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T1 - Syringaresinol causes vasorelaxation by elevating nitric oxide production through the phosphorylation and dimerization of endothelial nitric oxide synthase

AU - Chung, Byung Hee

AU - Kim, Sookon

AU - Kim, Jong Dai

AU - Lee, Jung Joon

AU - Baek, Yi Yong

AU - Jeoung, Dooil

AU - Lee, Hansoo

AU - Choe, Jongseon

AU - Ha, Kwon Soo

AU - Won, Moo Ho

AU - Kwon, Young Guen

AU - Kim, Young Myeong

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N2 - Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in vascular functions, including vasorelaxation. We here investigated the pharmacological effect of the natural product syringaresinol on vascular relaxation and eNOS-mediated NO production as well as its underlying biochemical mechanism in endothelial cells. Treatment of aortic rings from wild type, but not eNOS -/- mice, with syringaresinol induced endothelium-dependent relaxation, which was abolished by addition of the NOS inhibitor N G -monomethyl-L-arginine. Treatment of human endothelial cells and mouse aortic rings with syringaresinol increased NO production, which was correlated with eNOS phosphorylation via the activation of Akt and AMP kinase (AMPK) as well as elevation of intracellular Ca 2+ levels. A phospholipase C (PLC) inhibitor blocked the increases in intracellular Ca 2+ levels, AMPK-dependent eNOS phosphorylation, and NO production, but not Akt activation, in syringaresinol- treated endothelial cells. Syringaresinol-induced AMPK activation was inhibited by co-treatment with PLC inhibitor, Ca 2+ chelator, calmodulin antagonist, and CaMKKβ siRNA. This compound also increased eNOS dimerization, which was inhibited by a PLC inhibitor and a Ca 2+ -chelator. The chemicals that inhibit eNOS phosphorylation and dimerization attenuated vasorelaxation and cGMP production. These results suggest that syringaresinol induces vasorelaxation by enhancing NO production in endothelial cells via two distinct mechanisms, phosphatidylinositol 3-kinase/Akt- and PLC/Ca 2+ /CaMKKβ-dependent eNOS phosphorylation and Ca 2+ -dependent eNOS dimerization.

AB - Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in vascular functions, including vasorelaxation. We here investigated the pharmacological effect of the natural product syringaresinol on vascular relaxation and eNOS-mediated NO production as well as its underlying biochemical mechanism in endothelial cells. Treatment of aortic rings from wild type, but not eNOS -/- mice, with syringaresinol induced endothelium-dependent relaxation, which was abolished by addition of the NOS inhibitor N G -monomethyl-L-arginine. Treatment of human endothelial cells and mouse aortic rings with syringaresinol increased NO production, which was correlated with eNOS phosphorylation via the activation of Akt and AMP kinase (AMPK) as well as elevation of intracellular Ca 2+ levels. A phospholipase C (PLC) inhibitor blocked the increases in intracellular Ca 2+ levels, AMPK-dependent eNOS phosphorylation, and NO production, but not Akt activation, in syringaresinol- treated endothelial cells. Syringaresinol-induced AMPK activation was inhibited by co-treatment with PLC inhibitor, Ca 2+ chelator, calmodulin antagonist, and CaMKKβ siRNA. This compound also increased eNOS dimerization, which was inhibited by a PLC inhibitor and a Ca 2+ -chelator. The chemicals that inhibit eNOS phosphorylation and dimerization attenuated vasorelaxation and cGMP production. These results suggest that syringaresinol induces vasorelaxation by enhancing NO production in endothelial cells via two distinct mechanisms, phosphatidylinositol 3-kinase/Akt- and PLC/Ca 2+ /CaMKKβ-dependent eNOS phosphorylation and Ca 2+ -dependent eNOS dimerization.

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