Cyclic Nucleotide Phosphodiesterase 1C Promotes Human Arterial Smooth Muscle Cell Proliferation

Rybalkin, Sergei D.; Rybalkina, Irina G.; Beavo, Joseph A.; Bornfeldt, Karin E.

doi:10.1161/hh0202.104108

Cited by 112 publications

(102 citation statements)

References 37 publications

(45 reference statements)

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“…Also, it has been published that 8-MM-IBMX inhibits PDE5 (24), but furthermore, that this occurs at concentrations Ͼ 30 M (26, 37). To increase the selectivity of the inhibitor, we used a concentration of only 20 M of 8-MM-IBMX to reduce the influence on isoforms other than PDE1 (3,24,26,37). Although vinpocetine may be a less selective inhibitor of PDE1 than 8-MM-IBMX, it was also only effective after CaSR activation, and its effect was only slightly greater than that of the highly selective 8-MM-IBMX.…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

Ortiz-Capisano

Liao

Ortíz

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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release from the juxtaglomerular (JG) cell is stimulated by the second messenger cAMP and inhibited by calcium. We previously showed JG cells contain a calcium sensing receptor (CaSR), which, when stimulated, decreases cAMP formation and inhibits renin release. We hypothesize CaSR activation decreases cAMP and renin release, in part, by stimulating a calcium calmodulin-activated phosphodiesterase 1 (PDE1). We incubated our primary culture of JG cells with two selective PDE1 inhibitors [8-methoxymethil-IBMX (8-MM-IBMX; 20 M) and vinpocetine (40 M)] and the calmodulin inhibitor W-7 (10 M) and measured cAMP and renin release. Stimulation of the JG cell CaSR with the calcimimetic cinacalcet (1 M) resulted in decreased cAMP from a basal of 1.13 Ϯ 0.14 to 0.69 Ϯ 0.08 pM/mg protein (P Ͻ 0.001) and in renin release from 0.89 Ϯ 0.16 to 0.38 Ϯ 0.08 g ANG I/ml ⅐ h Ϫ1 ⅐ mg protein Ϫ1 (P Ͻ 0.001). However, the addition of 8-MM-IBMX with cinacalcet returned both cAMP (1.10 Ϯ 0.19 pM/mg protein) and renin (0.57 Ϯ 0.16 g ANG I/ml ⅐ h Ϫ1 ⅐ mg protein Ϫ1 ) to basal levels. Similar results were obtained with vinpocetine, and also with W-7. Combining 8-MM-IBMX and W-7 had no additive effect. To determine which PDE1 isoform is involved, we performed Western blot analysis for PDE1A, B, and C. Only Western blot analysis for PDE1C showed a characteristic band apparent at 80 kDa. Immunofluorescence showed cytoplasmic distribution of PDE1C and renin in the JG cells. In conclusion, PDE1C is expressed in isolated JG cells, and contributes to calcium's inhibitory modulation of renin release from JG cells.angiotensin; calmodulin; phosphodiesterase; cAMP; adenylyl cyclase RENIN IS THE RATE-LIMITING enzymatic step in the production of angiotensin, a hormone that integrates cardiovascular and renal function in the control of blood pressure as well as salt and volume homeostasis (33). Renin is produced by, stored in, and released from juxtaglomerular (JG) cells, which are derived from renin progenitor cells (42) and are located in the afferent arteriole near the hilus of the glomerulus (2, 43, 35). Two main intracellular second messenger systems are known to regulate renin synthesis and secretion: the cyclic nucleotide, cyclic adenosine monophosphate (cAMP) (8, 41), and intracellular calcium (Ca) (21).Renin secretion by the JG cells demonstrates a paradoxical inverse relationship with intracellular calcium concentration, such that millimolar changes in extracellular Ca or micromolar elevations in intracellular calcium retard renin release (1,9,14,20,22). The primary second messenger involved in the regulation of renin release is cAMP (8), and the concentration of cAMP in cells is determined by a balance between the rate of cAMP generation by adenylyl cyclases and cAMP hydrolysis by phosphodiesterases (PDE) (7, 16). We (30, 31), and also Grünberger et al. (18), have reported JG cells express calciuminhibitable adenylyl cyclase (27). Furthermore, we have identified the JG-specific isoform-regulating renin release to be adenylyl cyclase type V (30)...

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Section: Discussionmentioning

confidence: 99%

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

Ortiz-Capisano

Liao

Ortíz

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…PDE1A1 is selectively upregulated by chronic exposure to nitrates (192) and may contribute to nitrate tolerance. PDE1C is upregulated in proliferating human VSMCs and atherosclerotic lesions, and a PDE1 inhibitor suppresses proliferation (312). PDE1C mRNA and protein are also upregulated in pulmonary arterial vessels from patients with idiopathic pulmonary hypertension compared with vessels from healthy individuals and is a possible drug target for blocking vascular remodeling in these patients (270,329).…”

Section: Calmodulin-binding Phosphodiesterases (Pde1)mentioning

confidence: 99%

“…The need for potent selective PDE1 inhibitors is clear since PDE1 is linked to a role in the failing heart (389), cardiac hypertrophy (249), differentiation of monocytes in response to cytokines (31), VSMC proliferation (273,311,312), neurodegenerative diseases (244), and behavioral problems (185,349). Vinpocetine, the best known PDE1 inhibitor, has been used clinically in some places but has poor cell penetration properties and a significant toxicity profile.…”

Section: Pde1 Inhibitorsmentioning

confidence: 99%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

560

546

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The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

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“…A protein kinase A (PKA)-dependent phosphorylation of components involved in hormone-regulated activation of adenylyl cyclases contrib-utes to desensitization of cAMP-mediated effects in VSMCs ( Kohout and Lefkowitz, 2003). More recently, several reports have shown that increased cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) also plays a central role in desensitizing signaling through the cAMP signaling axis in several cells, including VSMCs (Rose et al, 1997;Mehats et al, 1999;Tilley and Maurice, 2002;Rybalkin et al, 2002;Maurice et al, 2003).…”

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confidence: 99%

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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Cyclic Nucleotide Phosphodiesterase 1C Promotes Human Arterial Smooth Muscle Cell Proliferation

Cited by 112 publications

References 37 publications

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

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

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