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Cardiovascular Research Advance Access first published online on February 21, 2009
This version [Corrected Proof] published online on March 30, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp065
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Stimulation of cGMP signalling protects coronary endothelium against reperfusion-induced intercellular gap formation

Sascha A. Kasseckert, Claudia Schäfer, Angelika Kluger, Dragan Gligorievski, Julia Tillmann, Klaus-Dieter Schlüter, Thomas Noll, Heinrich Sauer, Hans Michael Piper and Yaser Abdallah*

Institute of Physiology, Justus Liebig University, Aulweg 129, D-35392 Giessen, Germany

* Corresponding author. Tel: +49 6419947223; fax: +49 6419947219. E-mail address: yaser.abdallah{at}physiologie.med.uni-giessen.de

Aims: Ischaemia–reperfusion provokes barrier failure of the coronary microvasculature, impeding functional recovery of the heart during reperfusion. The aim of the present study was to investigate whether the stimulation of cGMP signalling by activation of soluble guanylyl cyclase (sGC) can reduce reperfusion-induced endothelial intercellular gap formation and to determine whether this is due to an influence on endothelial cytosolic Ca2+ homeostasis during reperfusion.

Methods and results: Experiments were performed with cultured coronary endothelial monolayers and isolated saline-perfused rat hearts. HMR1766 (1 µmol/L) or DEAnonoate (0.5 µmol/L) were used to activate sGC. After exposure to simulated ischaemic conditions, reperfusion of endothelial cells led to a pronounced increase in cytosolic calcium levels and intercellular gaps. Stimulation of cGMP signalling during reperfusion increased Ca2+ sequestration in the endoplasmic reticulum (ER) and attenuated the reperfusion-induced increase in cytosolic [Ca2+]. Phosphorylation of phospholamban was also increased, indicating a de-inhibition of the ER Ca2+ pump (SERCA). Reperfusion-induced intercellular gap formation was reduced. Reduction of myosin light chain phosphorylation indicated inactivation of the endothelial contractile machinery. Effects on cytsolic Ca2+ and gaps were abrogated by inhibition of cGMP-dependent protein kinase (PKG) with KT5823. In reperfused hearts, stimulation of cGMP signalling led to decreased oedema development.

Conclusion: sGC/PKG activation during reperfusion reduces reperfusion-induced endothelial intercellular gap formation by attenuation of cytosolic calcium overload and reduction of contractile activation in endothelial cells. This mechanism protects the heart against reperfusion-induced oedema.

KEYWORDS Reperfusion injury; Endothelium; Nitric oxide; cGMP; Protein kinase G

Time for primary review: 26 days

The original version was incorrect. The phrasing of the Abstract has been revised.

This paper was guest edited by Hiroshi Watanabe, Hamamatsu University School of Medicine.


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