Reduced Phosphodiesterase 3 Activity and Phosphodiesterase 3A Level in Synthetic Vascular Smooth Muscle Cells: Implications for Use of Phosphodiesterase 3 Inhibitors in Cardiovascular Tissues

Dunkerley, Heather A.; Tilley, Douglas G.; Palmer, Daniel; Liu, Hanguan; Jimmo, Sandra L.; Maurice, Donald H.

doi:10.1124/mol.61.5.1033

Cited by 33 publications

(37 citation statements)

References 41 publications

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“…First, our finding that PDE3 and PDE4 activities accounted for 50 and 35% of cAMP PDE activity in rat arteries, respectively, was different from our earlier reports, in which we showed that PDE3 and PDE4 activities represented 20 and 65% of cAMP PDE activity, respectively, in cultured rat aortic VSMC (Rose et al, 1997;Liu and Maurice, 1999;Liu et al, 2000). Recently, we showed that these differences were caused by a marked decrease in PDE3A upon culturing of these cells and that a similar reduction occurred when VSMC were activated in response to vascular injury in vivo (Dunkerley et al, 2002). Second, although the results of our study provide evidence that cAMP-elevating agents increased aortic and femoral artery VSMC PDE3 and PDE4 activities, the overall magnitude of the increases in vivo were significantly smaller than those achieved in cultured rat or human aortic VSMC (Rose et al, 1997;Liu et al, 2000).…”

Section: Discussioncontrasting

confidence: 53%

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Vascular Smooth Muscle Cell Phosphodiesterase (PDE) 3 and PDE4 Activities and Levels are Regulated by Cyclic AMP in Vivo

Tilley

Maurice

2002

Mol Pharmacol

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Prolonged incubation of several cell types, including cultured vascular smooth muscle cells (VSMC), with cyclic AMP-elevating agents increases cAMP phosphodiesterase (PDE) activity and levels. In this work, we describe for the first time an increase in arterial VSMC cAMP PDE activity and levels caused by cAMP-elevating agents when these agents are administered to rats in vivo. Injections of rats with dibutyryl cAMP (dbcAMP) or forskolin increased both PDE3 and PDE4 activities in aortic and femoral artery VSMC. Consistent with the idea that cAMPelevating agents increased PDE3 and PDE4 activities by acting directly on VSMC, local delivery of dbcAMP or forskolin to femoral arteries using a pluronic gel-based approach increased femoral artery VSMC PDE3 and PDE4 activities to levels similar to those observed after injection of these agents. Consistent with a role for de novo mRNA and protein synthesis in the cAMP-elevating agent induced increase in PDE3 and PDE4, 1) systemic administration of forskolin increased PDE3A, PDE3B, and PDE4D mRNA levels in aortic VSMC and femoral artery VSMC, 2) local delivery of dbcAMP increased PDE3A, PDE3B, and PDE4D3 protein levels in femoral artery VSMC, and 3) local administration of either actinomycin D or cycloheximide attenuated the effect of dbcAMP. In addition, our results indicate that the PDE3 and PDE4 variants increased by cAMP-elevating agents in arterial VSMC in situ were distinct from those elevated by these agents in cultured arterial VSMC. Consistent with the effect of increased VSMC cAMP PDE on blood vessel function, inhibition of PDE3 and PDE4 activities potentiated the relaxant effect of forskolin in dbcAMP-treated femoral artery rings to a greater extent than in untreated control blood vessels. We propose that our findings are consistent with the concept that cAMP regulates VSMC cAMP PDE activity and levels in vivo and that VSMC phenotype influences the choice of cAMP PDE variant that is elevated. Our findings are discussed in the context that agents aimed at specific PDE3 or PDE4 variants could perhaps allow greater control of cAMP-mediated regulation of VSMC behaviors that are phenotype-dependent.

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Section: Discussioncontrasting

confidence: 53%

“…Previous published work by our group (Liu and Maurice, 1998;Palmer and Maurice, 2000;Dunkerley et al, 2002), and results shown here (Fig. 1), demonstrate that the vast majority (Ͼ90%) of cells in rat aorta, or rat femoral artery, once cleaned of adherent connective tissue and fat, are medial VSMC.…”

Section: Resultsmentioning

confidence: 66%

Vascular Smooth Muscle Cell Phosphodiesterase (PDE) 3 and PDE4 Activities and Levels are Regulated by Cyclic AMP in Vivo

Tilley

Maurice

2002

Mol Pharmacol

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“…Serum starvation has been shown to modulate the phenotype of VSMCs from a synthetic/activated to a contractile/quiescent state (Li et al, 1999), a process known to involve chromatin remodeling, which adds credence to the notion that increased acetylation of CREs in the promoters of PDE4 genes can direct their transcription. It is interesting that the data presented here, in combination with our previous report demonstrating loss of PDE3A expression in rat synthetic/activated VSMCs (Dunkerley et al, 2002) and earlier reports of reduced soluble guanylyl cyclase and protein kinase G expression in synthetic/activated VSMCs (Anderson et al, 2000), may point to a more general phenotype-mediated reorganization of cyclic nucleotide signaling in these cells. Although provocative, the overall role that differential histone acetylation of the promoters controlling the expression of PDE3A, soluble guanylyl cyclase, and protein kinase G may play in these events remains to be assessed.…”

Section: Discussionsupporting

confidence: 50%

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

Tilley¹,

Maurice²

2005

Mol Pharmacol

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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.

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“…A7r5 cells natively express only Kv7.5 channels (Brueggemann et al, 2007, whereas MASMCs predominantly express Kv7.4/Kv7.5 channels (Brueggemann et al, , 2014a. Insensitivity of MASMC Kv7.4/7.5 channels to rolipram was replicated when this same subunit combination was expressed in A7r5 cells, suggesting that the difference in regulation of native Kv7 currents between A7r5 cells and MASMCs relates primarily to the Kv7 channel subunit stoichiometry rather than to differences in PDE isoforms (Polson and Strada, 1996;Dunkerley et al, 2002;Maurice et al, 2003).…”

Section: Discussionmentioning

confidence: 83%

Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

et al. 2015

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Kv7 (KCNQ) channels, formed as homo-or heterotetramers of Kv7.4 and Kv7.5 a-subunits, are important regulators of vascular smooth muscle cell (VSMC) membrane voltage. Recent studies demonstrate that direct pharmacological modulation of VSMC Kv7 channel activity can influence blood vessel contractility and diameter. However, the physiologic regulation of Kv7 channel activity is still poorly understood. Here, we study the effect of cAMP/protein kinase A (PKA) activation on whole cell K 1 currents through endogenous Kv7.5 channels in A7r5 rat aortic smooth muscle cells or through Kv7.4/Kv7.5 heteromeric channels natively expressed in rat mesenteric artery smooth muscle cells. The contributions of specific a-subunits are further dissected using exogenously expressed human Kv7.4 and Kv7.5 homo-or heterotetrameric channels in A7r5 cells. Stimulation of Ga scoupled b-adrenergic receptors with isoproterenol induced PKA-dependent activation of endogenous Kv7.5 currents in A7r5 cells. The receptor-mediated enhancement of Kv7.5 currents was mimicked by pharmacological agents that increase [cAMP] (forskolin, rolipram, 3-isobutyl-1-methylxanthine, and papaverine) or mimic cAMP (8-bromo-cAMP); the 2-to 4-fold PKA-dependent enhancement of currents was also observed with exogenously expressed Kv7.5 channels. In contrast, exogenously-expressed heterotetrameric Kv7.4/7.5 channels in A7r5 cells or native mesenteric artery smooth muscle Kv7.4/7.5 channels were only modestly enhanced, and homo-tetrameric Kv7.4 channels were insensitive to this regulatory pathway. Correspondingly, proximity ligation assays indicated that isoproterenol induced PKAdependent phosphorylation of exogenously expressed Kv7.5 channel subunits, but not of Kv7.4 subunits. These results suggest that signal transduction-mediated responsiveness of vascular smooth muscle Kv7 channel subunits to cAMP/PKA activation follows the order of Kv7.5 .. Kv7.4/Kv7.5 . Kv7.4.

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Reduced Phosphodiesterase 3 Activity and Phosphodiesterase 3A Level in Synthetic Vascular Smooth Muscle Cells: Implications for Use of Phosphodiesterase 3 Inhibitors in Cardiovascular Tissues

Cited by 33 publications

References 41 publications

Vascular Smooth Muscle Cell Phosphodiesterase (PDE) 3 and PDE4 Activities and Levels are Regulated by Cyclic AMP in Vivo

Vascular Smooth Muscle Cell Phosphodiesterase (PDE) 3 and PDE4 Activities and Levels are Regulated by Cyclic AMP in Vivo

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

Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

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