Sivaraman Vivek, Hausenloy Derek J, Kolvekar Shyam, Hayward Martin, Yap John, Lawrence David, Di Salvo Carmelo, Yellon Derek M
The Hatter Institute and Centre for Cardiology, University College London Hospital, 67 Chenies Mews, London WC1E6HX, UK.
J Mol Cell Cardiol. 2009 May;46(5):758-64. doi: 10.1016/j.yjmcc.2009.02.013. Epub 2009 Feb 25.
Experimental studies suggest that cardioprotection can be achieved through either the activation of PKC-epsilon prior to the index ischaemic episode or the inhibition of PKC-delta at the onset of reperfusion. However, whether these PKC isoforms exert such divergent roles in human myocardium, subjected to simulated ischaemia-reperfusion injury, is unclear. Human atrial trabeculae were isolated from right atrial appendages harvested from patients undergoing elective cardiac surgery. These were subjected to 90 min of hypoxia followed by 120 min of reoxygenation, at the end of which the recovery of baseline contractile function was determined. Atrial trabeculae were randomised to receive various treatment protocols comprising a peptide activator of PKC-epsilon, a peptide inhibitor of PKC-delta and their respective inactive control peptides. Administering the PKC-delta peptide inhibitor at reoxygenation improved the recovery of function at all the concentrations tested (39.3+/-1.4% at 5 nM, 52.4+/-2.9% at 50 nM and 46.8+/-2.9% at 500 nM versus the control group, 27.5+/-1.4%: N > or = 6/group: P<0.02). Preconditioning with the PKC-epsilon peptide activator improved the recovery of function (40.0+/-0.8% at 50 nM and 49.7+/-3.1% at 500 nM versus the control group 27.5+/-1.4%: N > or = 6/group: P<0.02). This cardioprotective effect was comparable to that achieved by a standard hypoxic preconditioning protocol (52.3+/-3.2%). Interestingly, administering the PKC-epsilon activator (500 nM) at the onset of reperfusion also improved the recovery of contractile function (40.7+/-2.1% versus 27.5+/-1.5%: N > or = 6/group: P < 0.05). In human myocardium, cardioprotection can be achieved by either inhibiting PKC-delta or activating PKC-epsilon at the onset of reperfusion. In addition, PKC-epsilon activation offers cardioprotection when administered as a preconditioning strategy.
实验研究表明，可通过在缺血发作前激活蛋白激酶C-ε（PKC-ε）或在再灌注开始时抑制蛋白激酶C-δ（PKC-δ）来实现心脏保护。然而，在遭受模拟缺血再灌注损伤的人体心肌中，这些PKC亚型是否发挥如此不同的作用尚不清楚。从接受择期心脏手术患者的右心耳中分离出人心房小梁。将其置于缺氧90分钟，随后再复氧120分钟，在此结束时测定基线收缩功能的恢复情况。将心房小梁随机分组，接受各种治疗方案，包括PKC-ε的肽激活剂、PKC-δ的肽抑制剂及其各自的无活性对照肽。在复氧时给予PKC-δ肽抑制剂在所有测试浓度下均改善了功能恢复（5 nM时为39.3±1.4%，50 nM时为52.4±2.9%，500 nM时为46.8±2.9%，而对照组为27.5±1.4%：每组N≥6：P<0.02）。用PKC-ε肽激活剂进行预处理可改善功能恢复（50 nM时为40.0±0.8%，500 nM时为49.7±3.1%，而对照组为27.5±1.4%：每组N≥6：P<0.02）。这种心脏保护作用与标准缺氧预处理方案所达到的效果相当（52.3±3.2%）。有趣的是，在再灌注开始时给予PKC-ε激活剂（500 nM）也改善了收缩功能的恢复（40.7±2.1%对27.5±1.5%：每组N≥6：P<0.05）。在人体心肌中，可通过在再灌注开始时抑制PKC-δ或激活PKC-ε来实现心脏保护。此外，当作为预处理策略给药时，PKC-ε激活可提供心脏保护作用。
