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

Sascha A Kasseckert1, Claudia Schäfer, Angelika Kluger

  • 1Institute of Physiology, Justus Liebig University, Aulweg 129, D-35392 Giessen, Germany.

Cardiovascular Research
|February 24, 2009
PubMed

Insights

Stimulating soluble guanylyl cyclase (sGC) with cGMP signaling reduces heart reperfusion injury by preventing endothelial cell gaps and calcium overload. This protects the heart from edema.

Area of Science:

  • Cardiovascular Science
  • Cellular Biology
  • Pharmacology

Background:

  • Ischaemia-reperfusion injury damages the coronary microvasculature, hindering heart recovery.
  • Endothelial barrier failure, characterized by intercellular gaps, is a key issue during reperfusion.

Purpose of the Study:

  • To investigate if activating soluble guanylyl cyclase (sGC) via cGMP signaling reduces reperfusion-induced endothelial gap formation.
  • To determine if this protective effect involves modulation of endothelial cytosolic calcium (Ca2+) homeostasis.

Main Methods:

  • Experiments utilized cultured coronary endothelial monolayers and isolated saline-perfused rat hearts.
  • Soluble guanylyl cyclase (sGC) was activated using HMR1766 or DEAnonoate.
  • Cytosolic Ca2+ levels, intercellular gap formation, and protein phosphorylation were measured.

Main Results:

  • Reperfusion increased cytosolic Ca2+ and intercellular gaps in endothelial cells.
  • cGMP signaling activation during reperfusion enhanced Ca2+ sequestration in the endoplasmic reticulum (ER) and reduced cytosolic Ca2+ overload.
  • This led to reduced intercellular gap formation and myosin light chain phosphorylation, indicating decreased endothelial cell contraction.
  • Inhibition of cGMP-dependent protein kinase (PKG) abolished these effects.
  • Stimulating cGMP signaling decreased edema development in reperfused hearts.

Conclusions:

  • Activation of the sGC/PKG pathway during reperfusion mitigates endothelial intercellular gap formation.
  • This protection is achieved by attenuating cytosolic calcium overload and reducing endothelial cell contractile activation.
  • This mechanism offers protection against reperfusion-induced heart edema.
Abstract

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