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Research ArticleArticle

Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function

Douglas G. Tilley and Donald H. Maurice
Molecular Pharmacology September 2005, 68 (3) 596-605; DOI: https://doi.org/10.1124/mol.105.014126
Douglas G. Tilley
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Donald H. Maurice
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Abstract

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. Although 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” VSMCs, distinct PDE4D gene variants coordinate these events 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, whereas the protein kinase A/cAMP response element-binding protein/cAMP response element 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 VSMCs. 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.

  • Received April 22, 2005.
  • Accepted June 2, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (3)
Molecular Pharmacology
Vol. 68, Issue 3
1 Sep 2005
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Research ArticleArticle

Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function

Douglas G. Tilley and Donald H. Maurice
Molecular Pharmacology September 1, 2005, 68 (3) 596-605; DOI: https://doi.org/10.1124/mol.105.014126

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Research ArticleArticle

Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function

Douglas G. Tilley and Donald H. Maurice
Molecular Pharmacology September 1, 2005, 68 (3) 596-605; DOI: https://doi.org/10.1124/mol.105.014126
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