Effects of soluble guanylate cyclase activation on heart transplantation in a rat model

Sivakkanan Loganathan, Sevil Korkmaz-Icöz, T. Radovits, Shiliang Li, Beatrice Mikles, Eniko Barnucz, Kristóf Hirschberg, Matthias Karck, G. Szabó

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is an important key mechanism to protect the heart from ischemia/reperfusion injury. However, this pathway is disrupted in several cardiovascular diseases as a result of decreased NO bioavailability and increased NO-insensitive forms of sGC. Cinaciguat preferentially activates these NO-insensitive, oxidized forms of sGC. Methods We assessed the hypothesis that targeting NO-unresponsive sGC would protect the graft against ischemia/reperfusion injury in a rat heart transplantation model. Before explantation, donor Lewis rats received methylcellulose (1%) vehicle or cinaciguat 10 mg/kg. The hearts were excised, stored in cold preservation solution, and heterotopically transplanted. We evaluated in vivo left ventricular function of the graft. Results After transplantation, decreased left ventricular systolic pressure (77 ± 3 mm Hg vs 123 ± 13 mm Hg, p <0.05), dP/dtmax (1,703 ± 162 mm Hg vs 3,350 ± 444 mm Hg, p <0.05), and dP/dtmin (995 ± 110 mm Hg vs 1,925 ± 332 mm Hg, p <0.05) were significantly increased by cinaciguat. Coronary blood flow was significantly higher in the cinaciguat group compared with the control group. Additionally, cinaciguat increased adenosine triphosphate levels (1.9 ± 0.4 μmol/g vs 6.6 ± 0.8 μmol/g, p <0.05) and improved energy charge potential. After transplantation, increased c-jun messenger RNA expression was downregulated, whereas superoxide dismutase-1 and cytochrome-c oxidase mRNA levels were upregulated by cinaciguat. Cinaciguat also significantly decreased myocardial DNA strand breaks induced by ischemia/reperfusion during transplantation and reduced death of cardiomyocytes in a cellular model of oxidative stress. Conclusions By interacting with NO-unresponsive sGC, cinaciguat enhances the protective effects of the NO/cGMP pathway at different steps of signal transduction after global myocardial ischemia/reperfusion. Its clinical use as pre-conditioning agent could be a novel approach in cardiac surgery.

Original languageEnglish
Pages (from-to)1346-1353
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume34
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

Fingerprint

Heart Transplantation
Nitric Oxide
Transplantation
Cyclic GMP
Reperfusion Injury
Transplants
Myocardial Reperfusion
Messenger RNA
Methylcellulose
DNA Breaks
Soluble Guanylyl Cyclase
BAY 58-2667
Ventricular Pressure
Electron Transport Complex IV
Left Ventricular Function
Cardiac Myocytes
Biological Availability
Thoracic Surgery
Reperfusion
Myocardial Ischemia

Keywords

  • cinaciguat
  • heart transplantation
  • ischemia/reperfusion
  • nitric oxide
  • soluble guanylate cyclase
  • soluble guanylate cyclase activation

ASJC Scopus subject areas

  • Transplantation
  • Cardiology and Cardiovascular Medicine
  • Pulmonary and Respiratory Medicine
  • Surgery

Cite this

Effects of soluble guanylate cyclase activation on heart transplantation in a rat model. / Loganathan, Sivakkanan; Korkmaz-Icöz, Sevil; Radovits, T.; Li, Shiliang; Mikles, Beatrice; Barnucz, Eniko; Hirschberg, Kristóf; Karck, Matthias; Szabó, G.

In: Journal of Heart and Lung Transplantation, Vol. 34, No. 10, 01.10.2015, p. 1346-1353.

Research output: Contribution to journalArticle

Loganathan, Sivakkanan ; Korkmaz-Icöz, Sevil ; Radovits, T. ; Li, Shiliang ; Mikles, Beatrice ; Barnucz, Eniko ; Hirschberg, Kristóf ; Karck, Matthias ; Szabó, G. / Effects of soluble guanylate cyclase activation on heart transplantation in a rat model. In: Journal of Heart and Lung Transplantation. 2015 ; Vol. 34, No. 10. pp. 1346-1353.
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AU - Li, Shiliang

AU - Mikles, Beatrice

AU - Barnucz, Eniko

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N2 - Background The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is an important key mechanism to protect the heart from ischemia/reperfusion injury. However, this pathway is disrupted in several cardiovascular diseases as a result of decreased NO bioavailability and increased NO-insensitive forms of sGC. Cinaciguat preferentially activates these NO-insensitive, oxidized forms of sGC. Methods We assessed the hypothesis that targeting NO-unresponsive sGC would protect the graft against ischemia/reperfusion injury in a rat heart transplantation model. Before explantation, donor Lewis rats received methylcellulose (1%) vehicle or cinaciguat 10 mg/kg. The hearts were excised, stored in cold preservation solution, and heterotopically transplanted. We evaluated in vivo left ventricular function of the graft. Results After transplantation, decreased left ventricular systolic pressure (77 ± 3 mm Hg vs 123 ± 13 mm Hg, p <0.05), dP/dtmax (1,703 ± 162 mm Hg vs 3,350 ± 444 mm Hg, p <0.05), and dP/dtmin (995 ± 110 mm Hg vs 1,925 ± 332 mm Hg, p <0.05) were significantly increased by cinaciguat. Coronary blood flow was significantly higher in the cinaciguat group compared with the control group. Additionally, cinaciguat increased adenosine triphosphate levels (1.9 ± 0.4 μmol/g vs 6.6 ± 0.8 μmol/g, p <0.05) and improved energy charge potential. After transplantation, increased c-jun messenger RNA expression was downregulated, whereas superoxide dismutase-1 and cytochrome-c oxidase mRNA levels were upregulated by cinaciguat. Cinaciguat also significantly decreased myocardial DNA strand breaks induced by ischemia/reperfusion during transplantation and reduced death of cardiomyocytes in a cellular model of oxidative stress. Conclusions By interacting with NO-unresponsive sGC, cinaciguat enhances the protective effects of the NO/cGMP pathway at different steps of signal transduction after global myocardial ischemia/reperfusion. Its clinical use as pre-conditioning agent could be a novel approach in cardiac surgery.

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