Laboratory for Experimental and Molecular Cardiology, TU Dresden, Dresden, Germany.
Institute for Clinical Chemistry and Laboratory Medicine, TU Dresden, Dresden, Germany; and.
J Cardiovasc Pharmacol. 2021 Mar 1;77(3):378-385. doi: 10.1097/FJC.0000000000000969.
The calcium sensitizer levosimendan is indicated for the hemodynamic stabilization of patients with acutely decompensated heart failure and has been shown to be protective against reperfusion injury after myocardial infarction. However, affected forms of cell death and underlying signaling pathways remain controversial. Therefore, the aim of this study was to examine the influence of levosimendan preconditioning and postconditioning on anoxia/reoxygenation-induced apoptosis, necrosis, and autophagy in H9c2 myoblasts. To mimic conditions of myocardial ischemia/reperfusion, rat cardiac H9c2 myoblasts were exposed to anoxia/starvation, followed by reoxygenation/refeeding. Apoptosis, necrosis, autophagy, cell viability, survival signaling, and mitochondrial permeability transition pore (mPTP) opening were measured. Both, pharmacological preconditioning and postconditioning with levosimendan were capable to reduce apoptosis as well as necrosis in stressed H9c2 cells. However, preconditioning showed to have the stronger impact compared with postconditioning. Moreover, levosimendan preconditioning increased autophagy, suggesting enhanced repair processes initiated by the early presence of the drug. Underlying mechanisms differ between both interventions: Although both are associated with PI3/Akt activation and reduced mPTP opening, only postconditioning but not preconditioning depended on mKATP activation. This variation might indicate that a pharmacological treatment after the onset of reoxygenation at least in part directly addresses mitochondrial structures for protection. In conclusion, we demonstrate that both pharmacological preconditioning and postconditioning with levosimendan protect anoxia/reoxygenation-stressed cells but differ in the underlying mechanisms. These results are decisive to obtain more insights into the beneficial effects of levosimendan in the treatment of reperfusion-mediated damage.
钙增敏剂左西孟旦用于急性失代偿性心力衰竭患者的血流动力学稳定，并且已被证明可防止心肌梗死后再灌注损伤。然而，受影响的细胞死亡形式和潜在的信号通路仍存在争议。因此，本研究旨在研究左西孟旦预处理和后处理对缺氧/复氧诱导的 H9c2 成肌细胞凋亡、坏死和自噬的影响。为了模拟心肌缺血/再灌注的条件，将大鼠心脏 H9c2 成肌细胞暴露于缺氧/饥饿，随后进行再氧合/再喂养。测量凋亡、坏死、自噬、细胞活力、存活信号和线粒体通透性转换孔 (mPTP) 开放。左西孟旦的药理学预处理和后处理均能减少应激 H9c2 细胞中的凋亡和坏死。然而，与后处理相比，预处理具有更强的影响。此外，左西孟旦预处理增加了自噬，表明药物早期存在时启动了增强的修复过程。这两种干预措施的潜在机制不同：虽然两者都与 PI3/Akt 激活和减少 mPTP 开放相关，但只有后处理而不是预处理依赖于 mKATP 激活。这种差异可能表明，再氧合开始后进行药理学治疗至少部分直接针对线粒体结构进行保护。总之，我们证明了左西孟旦的药理学预处理和后处理均可保护缺氧/复氧应激细胞，但潜在机制不同。这些结果对于深入了解左西孟旦在再灌注介导的损伤治疗中的有益作用至关重要。
