![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication April 22, 2005.
Revised June 2, 2005.
Accepted for publication June 2, 2005.
Sustained activation of adenylyl cyclase in vascular smooth muscle cells (VSMCs) results in the activation of a series of complex regulatory systems designed to desensitize these cells to further cAMP-mediated events. While an increase in Phosphodiesterase (PDE) 4-mediated hydrolysis of cAMP forms an integral part of this desensitization program in both "contractile/quiescent" and "synthetic/activated" VSMC, distinct PDE4D gene variants coordinate these event in these phenotypically distinct cells. Using a combination of pharmacological, biochemical and molecular biological approaches, and both in vivo and in vitro systems, we have identified the molecular basis underlying this VSMC phenotype-selective expression of PDE4D in response to cAMP-elevating agents in these cells. Thus, while the PKA/CREB/CRE signaling cascade regulates PDE4D expression in each VSMC phenotype, elevated levels of histone acetylation of the intronic promoter regulating PDE4D1 and PDE4D2 expression allows selective cAMP-mediated induction of expression of these PDE4D variants in "synthetic/activated". In contrast, the newly described EPAC1/Rap1A cAMP-dependent signaling cascade plays no role in regulating PDE4D expression in either VSMC phenotype. Our data are presented in the context of PDE4-mediated desensitization to cAMP-elevating agents in VSMCs and with the recognition that cAMP-elevating agents are being considered as adjunctive pharmacotherapy in percutaneous coronary interventions, including stenting.
Key words:
cAMP, Phosphodiesterases, Protein Kinase A, CREB, Ischemia/Reperfusion
This article has been cited by other articles:
|
|
 |
|
  S. J. Netherton, J. A. Sutton, L. S. Wilson, R. L. Carter, and D. H. Maurice Both Protein Kinase A and Exchange Protein Activated by cAMP Coordinate Adhesion of Human Vascular Endothelial Cells Circ. Res., October 12, 2007; 101(8): 768 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Levallet, J. Levallet, H. Bouraima-Lelong, and P.-J. Bonnamy Expression of the cAMP-Phosphodiesterase PDE4D Isoforms and Age-Related Changes in Follicle-Stimulating Hormone-Stimulated PDE4 Activities in Immature Rat Sertoli Cells Biol Reprod, May 1, 2007; 76(5): 794 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Houslay, G. S. Baillie, and D. H. Maurice cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling Circ. Res., April 13, 2007; 100(7): 950 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, J. R. Tang, Y. H. Choi, M. Napolitano, S. Hockman, M. Taira, E. Degerman, and V. C. Manganiello Importance of cAMP-response Element-binding Protein in Regulation of Expression of the Murine Cyclic Nucleotide Phosphodiesterase 3B (Pde3b) Gene in Differentiating 3T3-L1 Preadipocytes J. Biol. Chem., July 28, 2006; 281(30): 21096 - 21113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Houslay The Long and Short of Vascular Smooth Muscle Phosphodiesterase-4 As a Putative Therapeutic Target Mol. Pharmacol., September 1, 2005; 68(3): 563 - 567. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
