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Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells.
Circ Res. 2003 Sep 05; 93(5):406-13.CircR

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

Authors+Show Affiliations

University of Rochester, Center for Cardiovascular Research, 601 Elmwood Ave, Box 679, Rochester, NY 14642, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12919948

Citation

Aizawa, Toru, et al. "Role of Phosphodiesterase 3 in NO/cGMP-mediated Antiinflammatory Effects in Vascular Smooth Muscle Cells." Circulation Research, vol. 93, no. 5, 2003, pp. 406-13.
Aizawa T, Wei H, Miano JM, et al. Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res. 2003;93(5):406-13.
Aizawa, T., Wei, H., Miano, J. M., Abe, J., Berk, B. C., & Yan, C. (2003). Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circulation Research, 93(5), 406-13.
Aizawa T, et al. Role of Phosphodiesterase 3 in NO/cGMP-mediated Antiinflammatory Effects in Vascular Smooth Muscle Cells. Circ Res. 2003 Sep 5;93(5):406-13. PubMed PMID: 12919948.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. AU - Aizawa,Toru, AU - Wei,Heng, AU - Miano,Joseph M, AU - Abe,Jun-ichi, AU - Berk,Bradford C, AU - Yan,Chen, Y1 - 2003/08/14/ PY - 2003/8/16/pubmed PY - 2003/10/11/medline PY - 2003/8/16/entrez SP - 406 EP - 13 JF - Circulation research JO - Circ Res VL - 93 IS - 5 N2 - 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-kappaB-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-alpha-induced NF-kappaB-dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-kappaB 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-kappaB, 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-kappaB-dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-kappaB-mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-alpha-induced NF-kappaB-dependent reporter gene expression but also reduced endogenous NF-kappaB-dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-kappaB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/12919948/Role_of_phosphodiesterase_3_in_NO/cGMP_mediated_antiinflammatory_effects_in_vascular_smooth_muscle_cells_ L2 - https://www.ahajournals.org/doi/10.1161/01.RES.0000091074.33584.F0?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -