Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells

Zhu, Bing; Strada, Samuel J.; Stevens, Troy

doi:10.1152/ajplung.00433.2004

Cited by 55 publications

(60 citation statements)

References 41 publications

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“…More recently, ANP increased apoptosis and inhibited proliferation in RLMVEC in association with a sustained increase in cGMP (60). These results may differ from ours because of species differences between rat and mouse endothelial cells.…”

Section: Discussioncontrasting

confidence: 83%

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

Stephens

Rentsendorj

Servinsky

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Stephens RS, Rentsendorj O, Servinsky LE, Moldobaeva A, Damico R, Pearse DB. cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 299: L323-L333, 2010. First published May 7, 2010 doi:10.1152/ajplung.00442.2009.-Increasing evidence suggests that endothelial cytotoxicity from reactive oxygen species (ROS) contributes to the pathogenesis of acute lung injury. Treatments designed to increase intracellular cGMP attenuate ROSmediated apoptosis and necrosis in several cell types, but the mechanisms are not understood, and the effect of cGMP on pulmonary endothelial cell death remains controversial. In the current study, increasing intracellular cGMP by either 8pCPT-cGMP (50 M) or atrial natriuretic peptide (10 nM) significantly attenuated cell death in H2O2-challenged mouse lung microvascular (MLMVEC) monolayers. 8pCPT-cGMP also decreased perfusate LDH release in isolated mouse lungs exposed to H 2O2 or ischemia-reperfusion. The protective effect of increasing cGMP in MLMVECs was accompanied by enhanced endothelial H 2O2 scavenging (measured by H2O2 electrode) and decreased intracellular ROS concentration (measured by 2=,7=-dichlorofluorescin fluorescence) as well as decreased phosphorylation of p38 MAPK and Akt. The cGMP-mediated cytoprotection and increased H2O2 scavenging required Ͼ2 h of 8pCPT-cGMP incubation in wild-type MLMVEC and were absent in MLMVEC from protein kinase G (PKG I)Ϫ/Ϫ mice suggesting a PKGI-mediated effect on gene regulation. Catalase and glutathione peroxidase 1 (Gpx-1) protein were increased by cGMP in wild-type but not PKG IϪ/Ϫ MLMVEC monolayers. Both the cGMP-mediated increases in antioxidant proteins and H 2O2 scavenging were prevented by inhibition of translation with cycloheximide. 8pCPT-cGMP had minimal effects on catalase and Gpx-1 mRNA. We conclude that cGMP, through PKGI, attenuated H 2O2-induced cytotoxicity in MLMVEC by increasing catalase and Gpx-1 expression through an unknown posttranscriptional effect. apoptosis; necrosis; hydrogen peroxide; catalase; glutathione peroxidase INCREASED ENDOTHELIAL CELL DEATH from reactive oxygen species (ROS) contributes to the pathogenesis of acute lung injury (ALI) (56). Based on this concept, inhibition of apoptosis has been proposed as a potential ALI therapy (32). Unfortunately, the complex spectrum of cell death from the carefully orchestrated process of apoptosis to necrosis can result in unpredictable effects when specific cell death pathways are blocked (56). The pharmacological inhibition of ROS production (18) or the administration of endothelial-targeted antioxidant enzymes (53) may prove to be safer approaches to this problem, but these strategies have not yet translated into clinical therapies.In some clinical situations, an oxidant endothelial insult can be predicted in advance, allowing the potential for a preconditioning treatment to bolster endogenous antioxidant pathways (36). For example,...

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Section: Discussioncontrasting

confidence: 83%

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

Stephens

Rentsendorj

Servinsky

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In pulmonary endothelium (30,44,46,55,56) and epithelium (36), PDE2A, 3, 4, and 5 appear to represent the most significant forms. PDE2A is a dual-function PDE capable of hydrolyzing both cAMP and cGMP.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Rentsendorj

Damarla

Aggarwal

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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is stimulated by cGMP to hydrolyze cAMP, a potent endothelial barrier-protective molecule. We previously found that lung PDE2A contributed to a mouse model of ventilator-induced lung injury (VILI). The purpose of the present study was to determine the contribution of PDE2A in a two-hit mouse model of 1-day intratracheal (IT) LPS followed by 4 h of 20 ml/kg tidal volume ventilation. Compared with IT water controls, LPS alone (3.75 g/g body wt) increased lung PDE2A mRNA and protein expression by 6 h with a persistent increase in protein through day 4 before decreasing to control levels on days 6 and 10. Similar to the PDE2A time course, the peak in bronchoalveolar lavage (BAL) neutrophils, lactate dehydrogenase (LDH), and protein concentration also occurred on day 4 post-LPS. IT LPS (1 day) and VILI caused a threefold increase in lung PDE2A and inducible nitric oxide synthase (iNOS) and a 24-fold increase in BAL neutrophilia. Compared with a control adenovirus, PDE2A knockdown with an adenovirus expressing a short hairpin RNA administered IT 3 days before LPS/VILI effectively decreased lung PDE2A expression and significantly attenuated BAL neutrophilia, LDH, protein, and chemokine levels. PDE2A knockdown also reduced lung iNOS expression by 53%, increased lung cAMP by nearly twofold, and improved survival from 47 to 100%. We conclude that in a mouse model of LPS/VILI, a synergistic increase in lung PDE2A expression increased lung iNOS and alveolar inflammation and contributed significantly to the ensuing acute lung injury.lipopolysaccharide; ventilator-induced; cyclic guanosine monophosphate; inducible nitric oxide synthase; cAMP SEVERE PNEUMONIA IS A FREQUENT cause of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) (49). ARDS is characterized by neutrophil infiltration, the generation of toxic cytokines and reactive oxygen species (ROS), increased NO production and the loss of endothelial and epithelial barrier function (4). These features can be reproduced in animal models by the installation of intratracheal (IT) LPS (10, 24, 31), a key component of the gram-negative bacterial cell wall. LPS, through Toll-like receptor-4 signaling, was shown to cause increased NO from phosphorylated endothelial (eNOS) (11) and inducible nitric oxide synthase (iNOS) (24, 31) in alveolar macrophages, neutrophils, epithelium, and endothelium. NO from both eNOS and iNOS was found to play a major pathogenic role in ALI from LPS (24, 31, 42) and in ventilator-induced lung injury (VILI) (33, 39). These injurious effects of endogenous NO have been attributed to a reaction with superoxide to generate peroxynitrite (31, 33). In both LPS-induced ALI (47) and VILI (39), however, NO also activates soluble guanylyl cyclase (sGC), increasing production of cGMP in multiple cell types including endothelium (39), epithelium (9, 17), and macrophages (3).The effects of cGMP signaling in ALI are complex, depending on cell type, intracellular compartmentalization, and the downstream cGMP targets (39). These targets include...

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“…PDE6 is also found in pineal gland and certain melanoma cells (25,80). PDE5 is abundant in vascular and airway smooth muscle and platelets, but significant amounts also occur in cerebellar Purkinje cells, gastrointestinal epithelial cells, and endothelial cells (117,344,356,436). PDEs 7,8,9,10, and 11 are not widely expressed.…”

Section: B Diversity Of the Mammalian Phosphodiesterase Superfamilymentioning

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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Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells

Cited by 55 publications

References 41 publications

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

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