Activation of cGMP-stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelet aggregation

Dickinson, Natalie; Jang, Elliott K.; Haslam, Richard J.

doi:10.1042/bj3230371

Cited by 83 publications

(67 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In platelets or adrenal glomerulosa cells, increased cGMP levels resulting from NO or ANP, activated PDE2, and reduced cAMP. [27][28][29][30] In line with this, previous studies have shown that increased cAMP levels blocked superoxide formation in neutrophils 31 and that the nonhydrolyzable S(p)-cAMPS decreased the levels of activated Rac1 by inhibition of the Rac1-specific guanine nucleotide exchange factor p-Rex1. 32 However, inhibition of other cAMP-hydrolyzing PDEs, namely PDE3 or PDE4, decreased ROS generation in isolated rat glomeruli 33 or in mesangial cells.…”

Section: Pde2 Stimulates Formation Of Ros Via Rac1 and Nox2supporting

confidence: 59%

Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2

Diebold

Djordjevic

Petry

et al. 2009

Circulation Research

View full text Add to dashboard Cite

Abstract-Cyclic nucleotide phosphodiesterases (PDEs) control the levels of the second messengers cAMP and cGMP in many cell types including endothelial cells. Although PDE2 has the unique property to be activated by cGMP but to hydrolyze cAMP, its role in endothelial function is only poorly understood. Reactive oxygen species (ROS) have been recognized as signaling molecules controlling many endothelial functions. We thus investigated whether PDE2 would link to ROS generation and proliferative responses in human umbilical vein endothelial cells in response to thrombin. Thrombin stimulated the GTPase Rac1, known to activate NADPH oxidases, and enhanced ROS formation, whereas PDE2 inhibition or depletion by short hairpin (sh)RNA prevented these responses. Similar observations were made with 8-Br-cGMP or atrial natriuretic peptide. In agreement, thrombin elevated cGMP but decreased cAMP levels, whereas db-cAMP or forskolin diminished Rac1 activity and ROS production. Subsequently, PDE2 overexpression activated Rac1, increased ROS generation, and enhanced proliferation and in vitro capillary formation. These responses were not observed in the presence of inactive Rac1 or shRNA against the NADPH oxidase subunit NOX2. Inhibition or depletion of PDE2 also prevented thrombin-induced proliferation and capillary formation. Importantly, downregulation of PDE2 by lentiviral shRNA or PDE2 inhibition prevented vessel sprouting from mouse aortic explants and in vivo angiogenesis in a mouse model, respectively. In summary, PDE2 promotes activation of NADPH oxidase-dependent ROS production and subsequent endothelial proliferation and angiogenesis. Targeting PDE2 may provide a new therapeutic approach in diseases associated with endothelial dysfunction, oxidative stress, vascular proliferation, and angiogenesis.

show abstract

Section: Pde2 Stimulates Formation Of Ros Via Rac1 and Nox2supporting

confidence: 59%

Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2

Diebold

Djordjevic

Petry

et al. 2009

Circulation Research

View full text Add to dashboard Cite

show abstract

“…PDE2 enzymes hydrolyze either cAMP or cGMP; hydrolysis is stimulated by cGMP binding to amino terminal allosteric regulatory sites known as GAF domains (Martinez et al, 2002). A role for PDE2 in regulating cGMPmediated effects in blood platelets (Dickinson et al, 1997), cardiomyocyte and VEC (Mery et al, 1995), and adrenal granulosa cells (Juilfs et al, 1997) have each been reported. Indeed, natriuretic peptides or organic nitrates/nitric oxide donors elevate cellular cGMP and activate PDE2 in some of these cells (Mery et al, 1995;Dickinson et al, 1997).…”

Section: Pde2mentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterase Activity, Expression, and Targeting in Cells of the Cardiovascular System

Maurice¹,

Palmer²,

Tilley³

et al. 2003

Mol Pharmacol

293

255

View full text Add to dashboard Cite

Cyclic AMP (cAMP) and cGMP regulate a myriad of cellular functions, such as metabolism, contractility, motility, and transcription in virtually all cell types, including those of the cardiovascular system. Considerable effort over the last 20 years has allowed identification of the cellular components involved in the synthesis of cyclic nucleotides, as well as effectors of cyclic nucleotide-mediated signaling. More recently, a central role for cyclic nucleotide phosphodiesterase (PDE) has also been elaborated in many cell types, including those involved in regulating the activities of the cardiovascular system. In this review, we introduce the PDE families whose members are expressed in cells of the cardiovascular system including cardiomyocytes, vascular smooth muscle cells, and vascular endothelial cells. Because cell behavior is a dynamic process influenced by numerous factors, we will attempt to emphasize how changes in the activity, expression, and targeting of PDE influence cyclic nucleotide-mediated regulation of the behavior of these cells.The cyclic nucleotides cAMP and cGMP regulate a myriad of cellular functions, including metabolism, contractility, motility, and transcription in virtually all cell types, including those of the cardiovascular system (Antoni, 2000;Klein, 2002). Although early work identified cAMP and cGMP as second messengers and led to the discovery of the proteins involved in coordinating the synthesis, degradation, and cellular actions of cyclic nucleotides, early models describing how these systems allowed cyclic nucleotide-mediated regulation of multiple cellular functions underestimated the levels of flexibility and specialization involved. In this context, recent work has identified large numbers of receptor (Marchese et al., 1999;Lucas et al., 2000), adenylyl cyclase (Hanoune and Defer, 2001), guanylyl cyclase (Garbers, 1999;Lucas et al., 2000), heterotrimeric G-protein (Marchese et al., 1999), and cyclic nucleotide phosphodiesterase (PDE) (Beavo and Reifsnyder, 1990;Beavo, 1995;Conti et al., 1995;Manganiello and Degerman, 1999;Conti, 2000;Conti and Jin, 2000;Houslay and Kolch, 2000;Soderling and Beavo, 2000;Francis et al., 2001;Houslay and Adams, 2003) protein families. Although many of the cellular effects of cAMP and cGMP are coordinated through their activation of cyclic nucleotide-dependent protein kinases (Lincoln et al., 1995), several other effectors are now known. Thus, cyclic nucleotidegated ion channels (Yau, 1994), cAMP-activated guanine nucleotide exchange factors (de Rooij et al., 1998;Kawasaki et al., 1998), and cyclic nucleotide PDEs have each been shown to transduce cyclic nucleotide-encoded information (Beavo and Reifsnyder, 1990;Beavo, 1995;Conti et al., 1995;Manganiello and Degerman, 1999;Conti, 2000;Conti and Jin, 2000;Houslay and Kolch, 2000;Soderling and Beavo, 2000;Francis et al., 2001;Houslay and Adams, 2003). More recently, an appreciation of the impact of regulated anchoring/targeting of cyclic nucleotide-regulated proteins to discrete subcell...

show abstract

“…This cross-talk between the cGMP and cAMP pathways probably occurs in other cellular settings as well. For example, in platelets it is thought that high levels of NO elicit high cGMP accumulation that activates PDE2 and reduces cAMP (Dickinson et al, 1997;Dunkern and Hatzelmann, 2005). However, at lower cGMP levels PDE2 inhibitors alone have little effect on platelet aggregation in comparison to PDE3 inhibitors as PDE3 seems to play a more prominent role in cAMP regulation under these conditions.…”

mentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

2006

View full text Add to dashboard Cite

Activation of cGMP-stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelet aggregation

Cited by 83 publications

References 25 publications

Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2

Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2

Cyclic Nucleotide Phosphodiesterase Activity, Expression, and Targeting in Cells of the Cardiovascular System

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

Contact Info

Product

Resources

About