Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene

Andrea U. Steinbicker, Heling Liu, Kim Jiramongkolchai, Rajeev Malhotra, Elizabeth Y. Choe, Cornelius J. Busch, Amanda R. Graveline, Sonya M. Kao, Yasuko Nagasaka, Fumito Ichinose, Emmanuel S. Buys, Peter Brouckaert, Warren M. Zapol, Kenneth D. Bloch

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca 2+) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca 2+ channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca 2+ signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca 2+ in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel cross-talk mechanism between cGMP and cAMP signaling pathways.

Original languageEnglish (US)
Pages (from-to)294-302
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Volume25
Issue number3
DOIs
StatePublished - Oct 30 2011
Externally publishedYes

Keywords

  • Cyclic GMP
  • Nitric oxide
  • Protein kinase A
  • Vascular smooth muscle
  • cAMP-response element

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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