Regulation of cyclic AMP in rat pulmonary microvascular endothelial cells by rolipram-sensitive cyclic AMP phosphodiesterase (PDE4)

Thompson, W. J.; Ashikaga, Takashi; Kelly, John J.; Liu, Li; Zhu, Bing; Vemavarapu, Lakshimi; Strada, Samuel J.

doi:10.1016/s0006-2952(01)00914-5

Cited by 36 publications

(36 citation statements)

References 37 publications

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“…In addition, fewer studies have assessed the relative contributions of PDEs to cAMP-regulated cellular functions in microvascular endothelial cells than in VECs derived from larger blood vessels, especially in humans. In one report (Thompson et al, 2002), rat pulmonary microvascular endothelial cells were found to be devoid of cGMP PDE activity and to express cAMP-hydrolyzing PDE4 variants PDE4A and PDE4B. In contrast, our study demonstrates that HMVECs express significant PDE2 and PDE5 cGMP PDE activity and that PDE2, in addition to PDE4, each catalyzes cAMP hydrolysis.…”

Section: Discussioncontrasting

confidence: 62%

“…In contrast, our study demonstrates that HMVECs express significant PDE2 and PDE5 cGMP PDE activity and that PDE2, in addition to PDE4, each catalyzes cAMP hydrolysis. One commonality between our findings with HMVECs and those of Thompson et al (2002) is the dominance of PDE4 activity in these cells, although the individual PDE4 variants that account for this activity in rat and human were clearly different. Thus, although HMVECs expressed PDE4B2, an enzyme identified in rat pulmonary artery endothelial cells, HMVECs were shown to express significant PDE4D3 and PDE4D5, enzymes not found in rat cells.…”

Section: Discussionsupporting

confidence: 46%

“…In contrast, PDE5, PDE6, and PDE9 family enzymes selectively hydrolyze cGMP (Maurice et al, 2003). A limited number of studies have characterized PDE activities in VECs and shown that some bovine, rat, and human VECs contain activities consistent with expression of PDE1, PDE2, PDE3, PDE4, and PDE5 family enzymes (Lugnier and Schini, 1990;Ashikaga et al, 1997;Lugnier et al, 1999;Sadhu et al, 1999;Keravis et al, 2000;Miro et al, 2000;Thompson et al, 2002;Creighton et al, 2003;Favot et al, 2003;Maurice et al, 2003).…”

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confidence: 99%

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Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

Netherton

Maurice²

2004

Mol Pharmacol

113

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Angiogenesis is necessary during embryonic development and wound healing but can be detrimental in pathologies, including cancer. Because initiation of angiogenesis involves migration and proliferation of vascular endothelial cells (VECs) and cAMPelevating agents inhibit these events, such agents may represent a novel therapeutic avenue to controlling angiogenesis. Intracellular cAMP levels are regulated by their synthesis by adenylyl cyclases and hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). In this report, we show that human VECs express variants of PDE2, PDE3, PDE4, and PDE5 families and demonstrate that the levels of these enzymes differ in VECs derived from aorta, umbilical vein, and microvascular structures. Selective inhibition of PDE2 did not increase cAMP in any VECs, whether in the absence or presence of forskolin, but it did inhibit migration of all VECs studied. Inhibition of PDE4 activity decreased migration, and in conjunction with forskolin, increased cAMP in all VECs studied. PDE3 inhibition potentiated forskolin-induced increases in cAMP and inhibited migration in VECs derived from aorta and umbilical vein but not in microvascular VECs. In experiments with combinations of PDE2, PDE3, and PDE4 inhibitors, a complex interaction between the abilities of these agents to limit human VEC migration was observed. Overall, our data are consistent with the hypothesis that PDE subtype inhibition allows different effects in distinct VEC populations and indicate that these agents may represent novel therapeutic agents to limit angiogenesis in complex human diseases.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionsupporting

confidence: 46%

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confidence: 99%

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Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

Netherton

Maurice²

2004

Mol Pharmacol

113

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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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“…Such PKA activation phosphorylates tau-Ser214, reorganizes microtubules and disrupts the PMVEC barrier. [2, H] cAMP (Specific Activity 21.3 Ci/mmol) and Dowex-1X8-400 resin were prepared as described previously (Thompson et al, 2002). Pepstatin A and leupeptin were from Peninsula Laboratories.…”

Section: Journal Of Cell Science 121 (1)mentioning

confidence: 99%

Spectrin-anchored phosphodiesterase 4D4 restricts cAMP from disrupting microtubules and inducing endothelial cell gap formation

Creighton

Zhu

Alexeyev

et al. 2008

Journal of Cell Science

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Dynamic cAMP fluctuations that are restricted to a sub-plasma-membrane domain strengthen endothelial barrier integrity. Phosphodiesterases (PDEs) localize within this domain where they limit cAMP diffusion into the bulk cytosolic compartment; however, the molecular identity of PDEs responsible for endothelial cell membrane cAMP compartmentation remain poorly understood. Our present findings reveal that the D4 splice variant of the PDE4 phosphodiesterase family – PDE4D4 – is expressed in pulmonary microvascular endothelial cells, and is found in plasma membrane fractions. PDE4D4 interacts with αII spectrin within this membrane domain. Although constitutive PDE4D4 activity limits cAMP access to the bulk cytosol, inhibiting its activity permits cAMP to access a cytosolic domain that is rich in microtubules, where it promotes protein kinase A (PKA) phosphorylation of tau at Ser214. Such phosphorylation reorganizes microtubules and induces interendothelial cell gap formation. Thus, spectrin-anchored PDE4D4 shapes the physiological response to cAMP by directing it to barrier-enhancing effectors while limiting PKA-mediated microtubule reorganization.

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Regulation of cyclic AMP in rat pulmonary microvascular endothelial cells by rolipram-sensitive cyclic AMP phosphodiesterase (PDE4)

Cited by 36 publications

References 37 publications

Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

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

Spectrin-anchored phosphodiesterase 4D4 restricts cAMP from disrupting microtubules and inducing endothelial cell gap formation

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