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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 21, 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 signaling protects coronary endothelium against reperfusion-induced barrier failure

Sascha A. Kasseckert, Claudia Schäfer, Angelika Kluger, Dragan Gligorievski, Julia Tillmann, Thomas Noll, Heinrich Sauer, H. Michael Piper and Yaser Abdallah*

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

* Corresponding Author: Dr. Yaser Abdallah, Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, D-35392 Giessen, Germany, Tel.: ++496419947241, Fax.: ++496419947219, Email: yaser.abdallah{at}physiologie.med.uni-giessen.de

Aim: Ischemia-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 stimulation of cGMP signaling by activation of soluble guanylyl cyclase (sGC) can reduce reperfusion-induced endothelial barrier failure and to determine if this is due to an influence on endothelial cytosolic Ca2+ homeostasis during reperfusion.

Methods: Experiments were performed with cultured coronary endothelial monolayers and isolated saline-perfused rat hearts. HMR1766 (1µmol/L) or DEAnonoate (0.5µmol/L) were used to activate sGC.

Results: After exposure to simulated ischemic conditions, reperfusion of endothelial cells led to a pronounced increase in cytosolic calcium levels and intercellular gaps. Stimulation of cGMP signaling 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 signaling led to decreased edema development.

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

KEYWORDS reperfusion injury; endothelium; nitric oxide; cGMP; protein kinase G

Time for primary review: 26 Days


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