Effects of soluble guanylate cyclase activation on heart transplantation in a rat model
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 bioa...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
11 June 2015
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| In: |
The journal of heart and lung transplantation
Year: 2015, Volume: 34, Issue: 10, Pages: 1346-1353 |
| ISSN: | 1557-3117 |
| DOI: | 10.1016/j.healun.2015.05.006 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.healun.2015.05.006 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1053249815012772 
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| Author Notes: | Sivakkanan Loganathan, MD, Sevil Korkmaz-Icöz, PhD, Tamás Radovits, MD, PhD, Shiliang Li, MD, Beatrice Mikles, EnikőBarnucz, MD, Kristóf Hirschberg, MD, PhD, Matthias Karck, MD, and Gábor Szabó, MD, PhD |
| Summary: | 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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| Item Description: | Gesehen am 02.06.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3117 |
| DOI: | 10.1016/j.healun.2015.05.006 |