Slagsvold Katrine H, Moreira Jose B N, Rognmo Oivind, Høydal Morten, Bye Anja, Wisløff Ulrik, Wahba Alexander
K.G. Jebsen Center of Exercise in Medicine, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; Department of Cardiothoracic Surgery, St. Olav's University Hospital, Trondheim, Norway.
K.G. Jebsen Center of Exercise in Medicine, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; Norwegian Council on Cardiovascular Disease, Norway.
Int J Cardiol. 2014 Dec 15;177(2):409-17. doi: 10.1016/j.ijcard.2014.09.206. Epub 2014 Oct 14.
Understanding the intracellular mechanisms induced by remote ischemic preconditioning (RIPC) in the human left ventricle opens new possibilities for development of pharmacological cardioprotection against ischemia and reperfusion injury. In this study we investigated the effects of RIPC on mitochondrial function, activation of pro-survival protein kinase Akt and microRNA expression in left ventricular biopsies from patients undergoing coronary artery bypass surgery (CABG).
Sixty patients were randomized to control (n=30) or RIPC (n=30). A blood pressure cuff was applied to the arm of all patients preoperatively. The cuff remained deflated in control group, whereas RIPC was performed by 3 cycles of cuff inflation to 200 mm Hg for 5 min, separated by 5 min deflation intervals. Left ventricular biopsies were obtained before and 15 min after aortic declamping. The primary outcome was mitochondrial respiration measured in situ. Secondary outcomes were activation of protein kinase Akt, assessed by western immunoblotting, and expression of microRNAs assessed by array and real-time polymerase chain reaction.
Mitochondrial respiration was preserved during surgery in patients receiving RIPC (+0.2 μmol O2/min/g, p=0.69), and reduced by 15% in controls (-1.5 μmol O2/min/g, p=0.02). Furthermore, RIPC activated protein kinase Akt before aortic clamping (difference from control +43.3%, p=0.04), followed by increased phosphorylation of Akt substrates at reperfusion (+26.8%, p<0.01). No differences were observed in microRNA expression.
RIPC preserves mitochondrial function and activates pro-survival protein kinase Akt in left ventricle of patients undergoing CABG. Modulation of mitochondrial function and Akt activation should be further explored as cardioprotective drug targets.
http://www.clinicaltrials.gov, unique identifier: NCT01308138.
了解远程缺血预处理（RIPC）在人左心室中诱导的细胞内机制为开发针对缺血再灌注损伤的药理学心脏保护开辟了新的可能性。在本研究中，我们调查了RIPC对接受冠状动脉旁路移植术（CABG）患者左心室活检中线粒体功能、促生存蛋白激酶Akt的激活以及微小RNA表达的影响。
60例患者被随机分为对照组（n = 30）或RIPC组（n = 30）。术前对所有患者的手臂使用血压袖带。对照组袖带保持放气状态，而RIPC组通过3个周期的袖带充气至200 mmHg持续5分钟，间隔5分钟放气来进行。在主动脉钳夹前和钳夹后15分钟获取左心室活检样本。主要结局是原位测量的线粒体呼吸。次要结局是通过western免疫印迹评估的蛋白激酶Akt的激活，以及通过阵列和实时聚合酶链反应评估的微小RNA的表达。
接受RIPC的患者在手术期间线粒体呼吸得以保留（+0.2 μmol O2/分钟/克，p = 0.69），而对照组降低了15%（-1.5 μmol O2/分钟/克，p = 0.02）。此外，RIPC在主动脉钳夹前激活了蛋白激酶Akt（与对照组相比差异为+43.3%，p = 0.04），随后在再灌注时Akt底物的磷酸化增加（+26.8%，p < 0.01）。微小RNA表达未观察到差异。
RIPC可保留接受CABG患者左心室的线粒体功能并激活促生存蛋白激酶Akt。线粒体功能和Akt激活的调节应作为心脏保护药物靶点进一步探索。
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