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(Circulation Research. 2003;93:406.)
© 2003 American Heart Association, Inc.

Molecular Medicine

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

From the University of Rochester, Center for Cardiovascular Research, Rochester, NY.

Correspondence to Chen Yan, PhD, University of Rochester, Center for Cardiovascular Research, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail chen_yan{at}urmc.rochester.edu

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-B–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-–induced NF-B–dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-B 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-B, 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-B–dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-B–mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-–induced NF-B–dependent reporter gene expression but also reduced endogenous NF-B–dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-B–dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs.

Key Words: nitric oxide • nuclear factor-B • cGMP • phosphodiesterases

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