Valproic acid increases NO production via the SH-PTP1-CDK5-eNOS-Ser116signaling cascade in endothelial cells and mice

Du Hyong Cho, Jung Hyun Park, Eun Joo Lee, Kyung Jong Won, Sang Hee Lee, Yang Hoon Kim, Soojin Hwang, Kyoung Ja Kwon, Chan Young Shin, Kee Ho Song, Inho Jo, Seol Heui Han

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24 Scopus citations


Valproic acid (VPA) with its inhibitory activity of histone deacetylase has been used in the treatment of epilepsy and bipolar disorder associated with cerebrovascular dysfunction. Because nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a role in the maintenance of vascular function, NO is likely to mediate VPAs drug effect, but its effect on NO production remains controversial. We investigated whether and how VPA regulates NO production in bovine aortic endothelial cells (BAECs) and mice. VPA increased NO production in BAECs, which was accompanied by a decrease in phosphorylation of eNOS at serine 116 (eNOS-Ser116) and cyclin-dependent kinase 5 at tyrosine 15 (CDK5-Tyr15). Ectopic expression of p25, a CDK5 activator, restored the VPA-inhibited eNOS-Ser116phosphorylation. In silico analysis revealed that the CDK5-Tyr15residue might be a substrate for SH2 domain-containing protein tyrosine phosphatase 1 (SH-PTP1), and CDK5 actually interacted with SH-PTP1. VPA increased SH-PTP1 expression and its activity. Stibogluconate, a specific SH-PTP1 inhibitor, reversed the VPA-inhibited phosphorylation of CDK5-Tyr15and eNOS-Ser116. Knockdown of SH-PTP1 using small interfering RNA also reversed all the observed effects of VPA. Finally, both serum NO level and acetylcholine-induced aortic relaxation increased in VPA-medicated male mice. These increases were accompanied by increased SH-PTP1 expression and decreased phosphorylation of CDK5-Tyr15and eNOS-Ser116in mouse aortas. In conclusion, VPA increases NO production by inhibiting the CDK5-Tyr15-eNOS-Ser116phosphorylation axis; this process is mediated by SH-PTP1. VPA may be useful in the treatment of NO-related cerebrocardiovascular diseases.

Original languageEnglish
Pages (from-to)96-106
Number of pages11
JournalFree Radical Biology and Medicine
StatePublished - Nov 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.


  • Cyclin-dependent kinase 5
  • Endothelial nitric oxide synthase
  • Free radicals
  • Histone deacetylase
  • Nitric oxide
  • SH2 domain-containing protein tyrosine phosphatase 1
  • Valproic acid


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