Rolle der löslichen Guanylatzyklase im Modell der Herztransplantation in der Ratte

Translated title of the contribution: Effects of soluble guanylate cyclase activation on heart transplantation in a rat model

S. Loganathan, S. Korkmaz-Icöz, T. Radovits, S. Li, B. Mikles, E. Barnucz, K. Hirschberg, M. Karck, G. Szabó

Research output: Contribution to journalArticle

Abstract

It is known that the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic-GMP 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. We assessed the hypothesis that targeting NO-unresponsive sGC would protect the graft against ischemia/reperfusion injury in a rat heart transplantation model. Prior to explantation, the donor Lewis rats received methylcellulose (1 %) vehicle or cinaciguat 10 mg/kg body weight. The hearts were excised, stored in cold preservation solution and heterotopically transplanted. We evaluated in vivo left ventricular (LV) function of the graft. After transplantation, decreased LV systolic pressure (77 ± 3 vs. 123 ± 13 mmHg, p <0.05), dP/dtmax (1703 ± 162 vs. 3350 ± 444 mmHg, p <0.05) and dP/dtmin (995 ± 110 vs. 1925 ± 332 mmHg, 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 ATP levels (1.9 ± 0.4 vs. 6.6 ± 0.8 µmol/g, p <0.05) and improved energy charge potential. After transplantation, increased c‑jun mRNA 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 cardiomyocyte death in a cellular model of oxidative stress. 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 preconditioning agent could be a novel approach in cardiac surgery.

Original languageGerman
Pages (from-to)1-7
Number of pages7
JournalZeitschrift fur Herz-, Thorax- und Gefasschirurgie
DOIs
Publication statusAccepted/In press - Jul 5 2016

Fingerprint

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

Keywords

  • Cinaciguat
  • Cyclic guanosine monophosphate
  • Heart transplantation
  • Ischemia/reperfusion injury
  • Protein kinase G

ASJC Scopus subject areas

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

Cite this

Rolle der löslichen Guanylatzyklase im Modell der Herztransplantation in der Ratte. / Loganathan, S.; Korkmaz-Icöz, S.; Radovits, T.; Li, S.; Mikles, B.; Barnucz, E.; Hirschberg, K.; Karck, M.; Szabó, G.

In: Zeitschrift fur Herz-, Thorax- und Gefasschirurgie, 05.07.2016, p. 1-7.

Research output: Contribution to journalArticle

Loganathan, S. ; Korkmaz-Icöz, S. ; Radovits, T. ; Li, S. ; Mikles, B. ; Barnucz, E. ; Hirschberg, K. ; Karck, M. ; Szabó, G. / Rolle der löslichen Guanylatzyklase im Modell der Herztransplantation in der Ratte. In: Zeitschrift fur Herz-, Thorax- und Gefasschirurgie. 2016 ; pp. 1-7.
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