Claire Lugnier

Centre National de la Recherche Scientifique

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Thérèse Keravis

Centre National de la Recherche Scientifique

Jean‐Jacques Bourguignon

Centre National de la Recherche Scientifique

J.C. Stoclet

Centre National de la Recherche Scientifique

Jean‐Claude Stoclet

Laboratoire d'Hydrodynamique

Alain Le Bec

Centre National de la Recherche Scientifique

Narcisse Komas

Institut Pasteur de Bangui

Hélène Justiniano

Laboratoire de Biophotonique et Pharmacologie

Abdurazzag Abusnina

Université de Strasbourg

Laure Favot

Université de Poitiers

Pierre Raboisson

Janssen (Belgium)

Cooperative Institutions

Centre National de la Recherche Scientifique

223

Inserm

155

Université de Strasbourg

141

Laboratoire de Biophotonique et Pharmacologie

Université Paris Cité

Laboratoire d'Innovation Thérapeutique

Hôpitaux Universitaires de Strasbourg

Laboratoire des Biomolécules

Laboratoire de Chimie Moléculaire

Hôpital Civil, Strasbourg

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Modulation of VEGF-induced endothelial cell cycle protein expression through cyclic AMP hydrolysis by PDE2 and PDE4

Thrombosis and Haemostasis (2004)

Laure Favot Thérèse Keravis Claire Lugnier

Summary Endothelial cell proliferation in response to VEGF plays an important role in physiological and pathological angiogenesis. The role of PDE2 and PDE4 in VEGF-induced proliferation in HUVEC was investigated: 1) VEGF increased cAMP-hydrolytic activity by up-regulating the expression of PDE2 and PDE4 isozymes; 2) VEGF increased progression in cell cycle with an increase in p42/p44 MAP kinase, cyclin A and cyclin D1 expressions and with a decrease in p21waf1/cip1 and p27kip1 expressions; 3) EHNA (20 µM), a selective PDE2 inhibitor, RP73401 (10 µM), a selective PDE4 inhibitor blocked the VEGF-induced increase in p42/p44 MAP kinase expression; 4) RP73401, but not EHNA, blocked the VEGF-induced increase in cyclin A and decrease in p27kip1 expressions; 5) EHNA, contrary to RP73401, enhanced the VEGF-induced increase of cyclin A and decrease of p27kip1. EHNA and RP73401 together blocked the VEGF-induced increase in cyclin D1 and decrease in p21waf1/cip1 expressions; Inhibition of VEGF-upregulated PDE2 and PDE4 reversed the VEGF-induced alterations in cell cycle protein expression, bringing back endothelial cells to a non-proliferating status. Consequently, PDE2 and PDE4 inhibitions were able to inhibit VEGF-induced endothelial cell proliferation by restoring cell cycle key protein expression, and might thus be useful in excessive angiogenesis. Furthermore, the differences between PDE2 and PDE4 effects may suggest compartmentalized effects.

EHNA

Cyclin A

Cyclin A2

10.1160/th03-12-0768

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Citations (59)

The Endocrine Function of the Heart: Physiology and Involvements of Natriuretic Peptides and Cyclic Nucleotide Phosphodiesterases in Heart Failure

Journal of Clinical Medicine (2019)

Claire Lugnier Alain Meyer Anne Charloux Emmanuel Andrès Bernard Gény

Besides pumping, the heart participates in hydro-sodium homeostasis and systemic blood pressure regulation through its endocrine function mainly represented by the large family of natriuretic peptides (NPs), including essentially atrial natriuretic (ANP) and brain natriuretic peptides (BNP). Under normal conditions, these peptides are synthesized in response to atrial cardiomyocyte stretch, increase natriuresis, diuresis, and vascular permeability through binding of the second intracellular messenger's guanosine 3',5'-cyclic monophosphate (cGMP) to specific receptors. During heart failure (HF), the beneficial effects of the enhanced cardiac hormones secretion are reduced, in connection with renal resistance to NP. In addition, there is a BNP paradox characterized by a physiological inefficiency of the BNP forms assayed by current methods. In this context, it appears interesting to improve the efficiency of the cardiac natriuretic system by inhibiting cyclic nucleotide phosphodiesterases, responsible for the degradation of cGMP. Recent data support such a therapeutic approach which can improve the quality of life and the prognosis of patients with HF.

10.3390/jcm8101746

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Citations (36)

Interaction of Calmodulin and Calcium Antagonists with [3H]Diltiazem and [3H]Nitrendipine Binding Sites

Journal of Cardiovascular Pharmacology (1988)

Paul Schaeffer Claire Lugnier J. C. Stoclet

The interaction of calmodulin antagonists and hydrophobic calcium antagonists with calmodulin and calcium antagonist ( [3H]nitrendipine and [3H]diltiazem) binding sites was investigated. The classical calmodulin antagonists calmidazolium, trifluorperazine, and W-7 were active at similar concentrations in the three experimental systems. The hydrophobic calcium antagonists prenylamine and bepridil, however, interacted with [3H]diltiazem binding at concentrations up to 50 times lower than their calmodulin inhibiting concentrations. The structural requirements for binding to calmodulin and to calcium channels are thus not identical for these hydrophobic drugs, suggesting that the calcium channel interacting properties of these antagonists are not a direct consequence of their calmodulin binding properties.

Nitrendipine

Bepridil

10.1097/00005344-198806124-00021

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Citations (12)

Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals.

HAL (Le Centre pour la Communication Scientifique Directe) (2009)

A. Abi-Gerges W. Richter Fabrice Lefebvre P. Mateo A. Varin

BETA (programming language)

Myocardial hypertrophy

Phosphodiesterase 3

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Short‐term or long‐term treatments with a phosphodiesterase‐4 (PDE4) inhibitor result in opposing agonist‐induced Ca²⁺ responses in endothelial cells

British Journal of Pharmacology (2008)

Manuel Campos‐Toimil Thérèse Keravis Francisco Orallo K. Takeda Claire Lugnier

Background and purpose: We previously reported that agonist‐induced rises in cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) in human umbilical vein endothelial cells (HUVEC) were inhibited after a short‐term (2 min) pre‐treatment with cAMP‐elevating agents. The aim of this work was to study the effects of longer term (8 h) pre‐treatment with dibutyryl‐cAMP (db‐cAMP) or rolipram, a specific inhibitor of phosphodiesterase‐4 (PDE4), on [Ca 2+ ] i , cAMP levels and PDE activity and expression in HUVEC. Experimental approach: [Ca 2+ ] i changes were measured in isolated HUVEC by Fura‐2 imaging. Intracellular cAMP levels and PDE4 activity were assessed by enzyme‐immunoassay and radio‐enzymatic assay, respectively. PDE expression was measured by northern and western blot analysis. Key results: Long‐term pre‐treatment of HUVEC with rolipram or db‐cAMP significantly increased ATP‐, histamine‐ and thrombin‐induced [Ca 2+ ] i rises. Short‐term pre‐treatment with rolipram was associated with an increase in cAMP, whereas long‐term pre‐treatment was associated with a decrease in cAMP. Long‐term pre‐treatment with rolipram or db‐cAMP induced a significant increase in PDE4 activity and the expression of 74 kDa‐PDE4A and 73 kDa‐PDE4B was specifically enhanced. All these effects were suppressed by cycloheximide. Conclusions and implications: Our data suggest that sustained inhibition of PDE4 by rolipram induced an increase in PDE4 activity, possibly as a compensatory mechanism to accelerate cAMP degradation and that PDE4A and PDE4B were implicated in the regulation of [Ca 2+ ] i . Thus, isozyme‐specific PDE4 inhibitors might be useful as therapeutic agents in diseases where [Ca 2+ ] i handling is altered, such as atherosclerosis, hypertension and tolerance to β‐adrenoceptor agonists.

Rolipram

PDE10A

Phosphodiesterase 3

Phosphodiesterase inhibitor

10.1038/bjp.2008.56

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Citations (52)

PDE inhibitors: a new approach to treat metabolic syndrome?

Current Opinion in Pharmacology (2011)

Claire Lugnier

Therapeutic approach

10.1016/j.coph.2011.09.012

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Citations (36)

Mechanism of the cardiovascular activity of laudanosine: comparison with papaverine and other benzylisoquinolines

British Journal of Pharmacology (1994)

Susana Chuliá M. Dolores Ivorra Claire Lugnier Elisabeth Gabau Vila M.A. Noguera

The activity of (±)‐laudanosine, a benzyltetrahydroisoquinoline alkaloid, was investigated in pithed rats and rat isolated aorta. Its effects on [ 3 H]‐prazosin, [ 3 H]‐(+)‐cis‐diltiazem and [ 3 H]‐nitrendipine binding to rat cerebral cortical membranes, and on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were investigated. The dose‐response curve to methoxamine (3–300 μg kg −1 , i.v.) in normotensive pithed rats was shifted to the right by (±)‐laudanosine, 3 and 6 mg kg −1 . (±)‐Laudanosine inhibited in a concentration‐dependent manner the contractile responses evoked by noradrenaline (NA 1 μ m ), depolarizing solution (KC1 80 μ m ) or depolarizing solution plus phentolamine (10 μ m ) in rat isolated aorta. The alkaloid appeared to be more potent against NA‐induced contractions. In Ca 2+ ‐free solution, (±)‐laudanosine (100 μ m ) inhibited the contraction evoked by NA and did not modify the phasic contractile response evoked by caffeine. The alkaloid did not modify the refilling of the intracellular Ca 2+ ‐stores sensitive to NA or caffeine. (±)‐Laudanosine inhibited [ 3 H]‐prazosin binding to cortical membranes and also inhibited [ 3 H]‐(+)‐cis‐diltiazem but with a lower potency. [ 3 H]‐nitrendipine binding was not affected by laudanosine. (±)‐Laudanosine does not have a significant effect on the different forms of PDEs isolated from bovine aorta. In contrast, compounds structurally related to this alkaloid such as papaverine and its derivatives, had a non‐selective or more specific inhibitory effect on these PDE forms. These differences can be explained on the basis of their structural features: the planarity of the isoquinoline ring (papaverine) facilitates the interaction with receptor sites, and the different position of the benzyl group does not modify the activity unless this position leads to the presence of a chiral centre (laudanosine). These results suggest that (±)‐laudanosine has a selective activity as an α 1 ‐adrenoceptor blocker. Its lack of action on different PDE forms provides us with information about a group of benzylisoquinolines that with small structural changes show a different effect on PDE‐forms isolated from vascular smooth muscle.

Nitrendipine

Methoxamine

Phenylephrine

Nisoldipine

10.1111/j.1476-5381.1994.tb17150.x

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Citations (35)

Efficient synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines by regioselective acylation

Tetrahedron Letters (2002)

Pierre Raboisson Dominique Schultz Claire Lugnier Jean‐Jacques Bourguignon

Dimethylaniline

10.1016/s0040-4039(02)02456-5

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Citations (14)

Actividad vascular de (-)-anonaina, (-)-roemerine y (-)-pukateine, tres 6a natural (R) -1,2-methylenedioxyaporphines con diferentes afinidades para los receptores adrenérgicos alfa 1-subtipos.

Manuel Valiente Pilar D’Ocón M.A. Noguera Bruce Cassels Niven Claire Lugnier

This work was supported by research grants from the Generalitat Valenciana (GV97-VS-23-66 and GV01 -292) ando in parto by the Presiden ti al Chair in Science (Chile. BKC). We thank the Instituto de Cooperacion Iberoamericana for supporting a collaborative project between the University ofValencia and the University of Chile.

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Cyclic GMP catabolism up-regulation in MRL/lpr lupus-prone mice is associated with organ remodeling

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2014)

Issaka Yougbaré Thérèse Keravis Abdurazzag Abusnina Marion Décossas Nicolas Schall

10.1016/j.bbadis.2014.03.001

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Citations (7)