Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria.
Int J Mol Sci. 2021 Oct 14;22(20):11064. doi: 10.3390/ijms222011064.
Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague-Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca-sensitivities of force production (pCa) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.
研究了雄性斯普拉格-道利大鼠缺血后左心室（LV）重构及其通过重复远程缺血预处理（rRIC）进行假设性预防。通过永久性结扎左前降支冠状动脉（LAD）诱发心肌梗死（MI），并在 MI 诱导后 4 或 6 周后测试梗死前和非梗死下 LV 区域的心肌特征。rRIC 通过每日进行三个周期的 5 分钟单侧后肢缺血和 5 分钟再灌注来诱导，从 LAD 闭塞后 4 周开始持续 2 周。假手术动物作为对照。超声心动图检查和侵入性血流动力学测量显示，在 MI 诱导后 4 至 6 周期间，在没有 rRIC 的情况下，LV 收缩功能发生明显变化（即，LVEF 从 52.8±2.1%降至 50±1.6%，均值±SEM，<0.05），在存在 rRIC 的情况下（即，LVEF 从 48.2±4.8%增加至 55.2±4.1%，<0.05）。6 周时，前 LV 壁的血管紧张素转换酶（ACE）活性约为假手术动物的 5 倍。缺血后 LV 中的血管紧张素转换酶 2（ACE2）活性增加了近两倍。rRIC 有效减轻了这些 ACE 和 ACE2 活性的增加。MI 诱导后 6 周时，LV 通透型心肌细胞的钙敏感性（pCa）增加，同时 1）两个 LV 区域的心肌钙蛋白 I（cTnI）和 2）前壁的心肌肌球蛋白结合蛋白 C（cMyBP-C）磷酸化降低。rRIC 使 pCa、cTnI 和 cMyBP-C 磷酸化正常化。总之，缺血后 LV 重构涉及 ACE 和 ACE2 活性的区域特异性改变，以及心肌细胞肌丝蛋白磷酸化和功能的改变。rRIC 具有预防这些改变和改善 MI 后 LV 功能的潜力。
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