Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells

Toru Aizawa, Heng Wei, Joseph M. Miano, Jun ichi Abe, Bradford C. Berk, Chen Yan

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Atherosclerosis involves cellular immune responses and altered vascular smooth muscle cell (VSMC) function. Nitric oxide (NO)/cGMP is uniquely capable of inhibiting key processes in atherosclerosis. In this study, we determined the effects of NO/cGMP and their molecular mechanisms in the regulation of NF-κB-dependent gene expression in VSMCs. We found that cGMP-elevating agents such as the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and C-type natriuretic peptide (CNP), reduced TNF-α-induced NF-κB-dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-κB are mediated by cAMP-dependent protein kinase (PKA) but not cGMP-dependent protein kinase (PKG) based on the findings that the selective PKA inhibitor, PKI, abolished the effects of SNAP and CNP on NF-κB, whereas the PKG inhibitor Rp-8-Br-PET-cGMP had no effect. Inhibition of cGMP-inhibited cAMP-hydrolyzing phosphodiesterase 3 (PDE3) blocked SNAP- and CNP-elicited effects on NF-κB-dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-κB-mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-α-induced NF-κB-dependent reporter gene expression but also reduced endogenous NF-κB-dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-κB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs.

Original languageEnglish (US)
Pages (from-to)406-413
Number of pages8
JournalCirculation research
Volume93
Issue number5
DOIs
StatePublished - Sep 5 2003
Externally publishedYes

Keywords

  • CGMP
  • Nitric oxide
  • Nuclear factor-κB
  • Phosphodiesterases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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