RT Journal Article
SR Electronic
T1 Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 596
OP 605
DO 10.1124/mol.105.014126
VO 68
IS 3
A1 Douglas G. Tilley
A1 Donald H. Maurice
YR 2005
UL http://molpharm.aspetjournals.org/content/68/3/596.abstract
AB 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.