Dimethylarginine dimethylaminohydrolase 1 modulates endothelial cell growth through nitric oxide and Akt

Ping Zhang, Xinli Hu, Xin Xu, Yingjie Chen, Robert J. Bache

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Objective- Dimethylarginine dimethylaminohydrolase 1 (DDAH1) modulates NO production by degrading the endogenous nitric oxide (NO) synthase (NOS) inhibitors asymmetrical dimethylarginine (ADMA) and L-NG-monomethyl arginine (L-NMMA). This study examined whether, in addition to degrading ADMA, DDAH1 exerts ADMA-independent effects that influence endothelial function. Methods and Results- Using selective gene silencing of DDAH1 with small interfering RNA and overexpression of DDAH1 in human umbilical vein endothelial cells, we found that DDAH1 acts to promote endothelial cell proliferation, migration, and tube formation by Akt phosphorylation, as well as through the traditional role of degrading ADMA. Incubation of human umbilical vein endothelial cells with the NOS inhibitors l-NG-nitro-arginine methyl ester (L-NAME) or ADMA, the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3-2)quinoxalin-1-one, or the cGMP analog 8-(4-Chlorophenylthio)-cGMP had no effect on phosphorylated (p)-Akt Ser473, indicating that the increase in p-Akt Ser473 produced by DDAH1 was independent of the NO-cGMP signaling pathway. DDAH1 formed a protein complex with Ras, and DDAH1 overexpression increased Ras activity. The Ras inhibitor manumycin-A or dominant-negative Ras significantly attenuated the DDAH1-induced increase in p-Akt Ser473. Furthermore, DDAH1 knockout impaired endothelial sprouting from cultured aortic rings, and overexpression of constitutively active Akt Ser473 or DDAH1 rescued endothelial sprouting in the aortic rings from these mice. Conclusion- DDAH1 exerts a unique role in activating Akt Ser473 that affects endothelial function independently of degrading endogenous NOS inhibitors.

Original languageEnglish (US)
Pages (from-to)890-897
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • angiogenesis
  • endothelial function
  • endothelium
  • nitric oxide
  • nitric oxide synthase
  • vascular biology

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