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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 20, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn251
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
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Transgenic myocardial overexpression of prokineticin receptor-2 (GPR73b) induces hypertrophy and capillary vessel leakage

Kyoji Urayama*, Deniz B. Dedeoglu*, Célia Guilini*, Stefan Frantz{dagger}, Georg Ertl{dagger}, Nadia Messaddeq{dagger}{dagger} and Canan G. Nebigil*,¶¶

* CNRS/ULP, UMR 7175-LC1, Ecole Supérieure de Biotechnologie de Strasbourg, Bld. Sébastien Brandt BP. 10413, F-67412 Illkirch, France
{dagger} Medizinsche Klinik und Poliklinik I, Herz-/Kreislaufzentrum, University Wurzburg, Wurzburg, Germany
{dagger}{dagger} Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/ULP UMR 7104, INSERM U596, BP. 10142, F-67404 Illkirch, France

¶¶ Author for correspondence: Canan G. Nebigil UMR 7175-LC1, CNRS/Strasbourg Universite-I, ESBS, Bld. Sébastien Brandt BP. 10413, F-67412 Illkirch, France (nebigil{at}esbs.u-strasbg.fr), Phone: 33 390 24 47 56 and Fax: 33 390 24 48 29

Aim: Prokineticins are small secreted bioactive molecules. They exert their biological activity by binding to two G protein coupled receptors. Previously, we have shown that overexpression of prokineticin receptor-1 (PKR1) in TG mice heart induced neovascularization. Since PKR1 and PKR2 are 85 % identical and expressed in cardiovascular tissues, we hypothesize that prokineticin receptor-2 (PKR2) may also contribute to cardiomyocyte growth and vascularization.

Methods and Results: We have generated transgenic (TG) mice overexpressing PKR2 in cardiomyocytes. TG mice exhibit increased hypertrophic gene expression and heart to body weight ratio accompanied with the increased length of cardiomyocytes size at the age of 12 weeks. Increased left ventricular end systolic and diastolic diameters, without cardiac dysfunction at the age of 24 weeks indicates that TG mice have an eccentric hypertrophy with compensated cardiac function. Quantitative morphological analysis showed that TG hearts have a normal micro vessel density and number of branch points. However, they exhibit increased abnormal endothelial cell shape and ultrastructure, changed cellular distribution of a tight junction protein zona occludens-1 (ZO-1), and vascular leakage in heart without a rise of angiogenic factor levels at early and late age. Application of media conditioned by H9c2 cardioblast cells overexpressing PKR2 significantly induced impaired ZO-1 localization in H5V endothelial cells, mimicking the TG model.

Conclusion: These findings provide the first genetic evidence that cardiomyocyte-PKR2 signaling leads to eccentric hypertrophy in an autocrine regulation, and impaired endothelial integrity in a paracrine regulation without inducing angiogenesis. These TG mice may provide a new genetic model for heart diseases.

Time for primary review: 33 days


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