Acute hypoxia to endothelial cells induces activating transcription factor 3 (ATF3) expression that is mediated via nitric oxide

Shih Chung Chen, Yu Chi Liu, Kou Gi Shyu, Danny Ling Wang

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


Endothelial cells (ECs) play an important role in hypoxia-induced vascular disorders. We investigated the acute hypoxia effect on endothelial expression of activating transcription factor 3 (ATF3), a stress-inducible transcription factor playing significant roles in cellular responses to stress. Bovine aortic ECs were subjected to acute hypoxia (1% O2, pO2 = 8 mmHg) and ATF3 expression was examined. ECs exposed to hypoxia transiently induced ATF3 expression. A transient increase in the activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in ECs was observed; however, only ECs pretreated with a specific inhibitor to JNK suppressed the hypoxia-induced ATF3 expression. ECs exposed to acute hypoxia transiently increased endothelial nitric oxide (eNOS) activity. Pre-treating ECs with a specific inhibitor to eNOS (l-NAME) or PI3-kinase significantly inhibited the hypoxia-induced JNK activation and ATF3 expression. ATF3 induction has been shown to inhibit matrix metalloproteinase-2 (MMP-2) expression. Consistently, ECs exposed to hypoxia attenuated the MMP-2 expression. This hypoxia-attenuated MMP-2 expression can be rescued by pre-treating ECs with an inhibitor of eNOS. These results suggest that the ATF3 induction by acute hypoxia is mediated by nitric oxide and the JNK pathway in ECs. Our findings provide a molecular basis for the mechanism in which ECs respond to acute hypoxia.

Original languageEnglish
Pages (from-to)281-288
Number of pages8
Issue number2
Publication statusPublished - Dec 2008


  • Activating transcription factor 3
  • Hypoxia
  • Matrix metalloproteinase-2
  • Mitogen-activated protein kinase
  • Nitric oxide
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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