Kakaei Yalda, Hussain Shafaat, Elmahdy Ahmed, Berger Evelin, Shekka Espinosa Aaron, Sevastianova Valentyna, Sheybani Zahra, Al-Awar Amin, Kalani Mana, Jha Sandeep, Zulfaj Ermir, Nejat Amirali, Jha Abhishek, Pylova Tetiana, Krasnikova Maryna, Andersson Erik Axel, Silva Vagner Ramon Rodrigues, Omerovic Elmir, Redfors Björn
Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Bruna stråket 16, SU/S, 41345, Gothenburg, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
Sci Rep. 2025 Apr 7;15(1):11836. doi: 10.1038/s41598-025-90735-4.
Myocardial ischemic preconditioning (IPC) enhances myocardial resilience to ischemic injury. Myocardial stunning is a transient, reversible dysfunction, while necrosis involves irreversible cell death. The relationship between IPC, stunning, and necrosis is not well understood, requiring further molecular investigation. This study aimed to investigate the proteomic changes associated with IPC, focusing on its relationship with myocardial stunning and necrosis. A novel 13.5-minute ischemia-reperfusion (I/R) rat model was specifically chosen to induce myocardial stunning, providing a unique approach to assess IPC effects in this context. Rats underwent either IPC with two 5-minute ischemia/reperfusion cycles followed by a 13.5-minute ischemic period or the procedure without IPC (no ischemic preconditioning, NIPC). Myocardial samples were collected at early (T1) and 4-hour post-reperfusion (T2) time points for proteomic analysis. Protein levels were quantified by differential labeling using TMTpro reagents, and subsequent liquid chromatography-mass spectrometry. IPC induced upregulation of proteins involved in endocytosis and Fc gamma R-mediated phagocytosis pathways at T1, while downregulating proteins related to tissue remodeling, immune response, and coagulation at T2. Conversely, NIPC exhibited upregulation of proteins associated with tissue damage and inflammation. IPC rats demonstrated enhanced leukocyte migration, complement activation, and immune response between T1 and T2. Consistent proteomic changes were observed between T1 and T2 in IPC vs. NIPC groups, and common alterations between IPC T2 vs. T1 and NIPC T2 vs. T1 comparisons underline shared pathways in cardiac complement and coagulation cascades. Our study reveals distinct proteomic changes induced by IPC in the context of myocardial stunning and necrosis. IPC activates early protective pathways, attenuates tissue damage and inflammation, and preserves myocardial function. These findings underscore IPC's reparative potential and identify myocardial stunning as an important, transient adaptation, which may have implications for supportive clinical management in I/R.
心肌缺血预处理（IPC）可增强心肌对缺血损伤的耐受性。心肌顿抑是一种短暂的、可逆性功能障碍，而坏死则涉及不可逆的细胞死亡。目前，对于IPC、心肌顿抑和坏死之间的关系尚不清楚，需要进一步进行分子层面的研究。本研究旨在探讨与IPC相关的蛋白质组学变化，重点关注其与心肌顿抑和坏死的关系。本研究特意选用了一种新型的13.5分钟缺血再灌注（I/R）大鼠模型来诱导心肌顿抑，从而提供一种独特的方法来评估在此背景下IPC的作用。大鼠接受了两种方案：一是经历两个5分钟缺血/再灌注周期的IPC，随后进行13.5分钟的缺血期；二是不进行IPC的操作（无缺血预处理，NIPC）。在再灌注早期（T1）和再灌注后4小时（T2）时间点采集心肌样本进行蛋白质组学分析。使用TMTpro试剂通过差异标记对蛋白质水平进行定量，随后进行液相色谱 - 质谱分析。IPC在T1时诱导参与内吞作用和FcγR介导的吞噬作用途径的蛋白质上调，而在T2时下调与组织重塑、免疫反应和凝血相关的蛋白质。相反，NIPC表现出与组织损伤和炎症相关的蛋白质上调。IPC大鼠在T1和T2之间表现出增强的白细胞迁移、补体激活和免疫反应。在IPC组与NIPC组的T1和T2之间观察到一致的蛋白质组学变化，IPC组T2与T1以及NIPC组T2与T1比较之间的共同改变突显了心脏补体和凝血级联反应中的共同途径。我们的研究揭示了在心肌顿抑和坏死背景下IPC诱导的不同蛋白质组学变化。IPC激活早期保护途径，减轻组织损伤和炎症，并保留心肌功能。这些发现强调了IPC的修复潜力，并确定心肌顿抑是一种重要的、短暂的适应性反应，这可能对I/R的支持性临床管理具有重要意义。
