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  • Reduction of the hydrolysis of ATP is an important strategy

    2021-09-16

    Reduction of the hydrolysis of ATP is an important strategy to reduce ischemia/reperfusion injury. Increased intracellular concentrations of solutes secondary to ATP depletion are known to result in osmotic swelling that may be sufficient to cause sarcolemmal rupture. Cinaciguat activates sGC directly and generates cGMP, which activates protein kinase G. The sequence of signaling was found to be opening of mitochondrial ATP-sensitive potassium channels. Opening of these taurolidine leads—several steps downstream this pathway—to an enhanced proton gradient at the mitochondrial membrane and to an increased mitochondrial ATP synthesis. Supporting this concept, our myocardial ATP levels, as a biochemical marker for myocardial energetics, confirmed a normalization of myocardial high-energy phosphate availability after heart transplantation by cinaciguat pre-conditioning. Moreover, myocardial cytochrome-c oxidase mRNA expression, as a terminal member of the mitochondrial chain, was upregulated in the cinaciguat-treated transplantation group, which additionally indicates that cinaciguat plays an important role in the mitochondrial ATP production. These results support the view that sGC activation by cinaciguat can restore myocardial energy balance and can inhibit the adverse effects of ATP depletion such as osmotic swelling, sarcolemmal rupture, and necrosis. Additionally, the regulation of the apoptotic signaling pathway seems to contribute to the cardioprotection of this sGC activator. A signal-transducing transcription factor of the AP-1 family, c-jun, has been linked to apoptosis. Continuous expression of c-jun and c-fos leads to programmed cell death after damage, whereas transient expression is hypothesized to be associated with regeneration. In the present study, the increased c-jun mRNA content in the transplant group was significantly downregulated after cinaciguat treatment, suggesting a decrease of apoptosis. The mitochondrial ATP-sensitive potassium channel opening property of cinaciguat may also contribute to its role in the inhibition of apoptosis. This thesis was confirmed by our TUNEL staining, which is sensitive to apoptosis. However, in the present setup, transforming growth factor-β1, a member of the growth factor family, and hypoxia-inducible factor-1α do not have significant influence. The present study has limitations. taurolidine The rat model of heart transplantation was selected to be a suitable model to evaluate graft dysfunction. The selected model of heterotopic heart transplantation is very similar to the well-known original Langendorff isolated perfused heart model. In contrast to the Langendorff model, the heart of the presently used model is perfused by blood in situ, and it can be interpretated as the next evolutionary step of the original Langendorff isolated perfused heart model. Nevertheless, it has some similar disadvantages that are already known from the Langendorff model. The left ventricle is perfused via the coronary circulation. Although this model is a beating heart model, the left ventricle is not filled with blood and does not eject blood. On one hand, this allows a faster recovery after ischemia/reperfusion making it hard to show differences between experimental groups after a certain time of reperfusion, and on the other hand, it leads to time-dependent mechanical deterioration and atrophy. Nevertheless, in detailed characterization studies using this model, it has been shown that major deterioration does not occur until at least 24 hours after implantation. Secondary to the effects of cinaciguat as an activator of sGC, it is also known to execute smooth muscle protection; this was shown in our previous studies.23, 24 In the present study, we showed an improved coronary blood flow. Improvement in vascular function can be partly responsible for enhanced myocardial protection secondary to improved coronary blood flow after ischemia/reperfusion. Also, direct protective effects of cinaciguat were proven by our in vitro cell culture experiments, which cannot be influenced by the vasoactive effects of cinaciguat. Nevertheless, using this in vivo model, it is impossible to state what percentage each of these effects contributes to the cardiac protection. Another limitation of the present study is that effects of immune activation that can be triggered by ischemia/reperfusion injury were not examined. Possible adverse effects of immune activation cannot be distinguished from ischemia/reperfusion itself.