Vascular smooth muscle cell phenotype-dependent phosphodiesterase 4D short form expression: role of differential histone acetylation on cAMP-regulated function.
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.
Tilley
Douglas G
DG
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
Maurice
Donald H
DH
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D000242:Cyclic AMP / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D017931:DNA Primers; D006657:Histones / Q000378:metabolism*; D007438:Introns; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D041681:NIH 3T3 Cells; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
D017931:DNA Primers; D006657:Histones; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4