Sanada S, Kitakaze M, Papst P J, Hatanaka K, Asanuma H, Aki T, Shinozaki Y, Ogita H, Node K, Takashima S, Asakura M, Yamada J, Fukushima T, Ogai A, Kuzuya T, Mori H, Terada N, Yoshida K, Hori M
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Circ Res. 2001 Feb 2;88(2):175-80. doi: 10.1161/01.res.88.2.175.
Although ischemic stress, including ischemic preconditioning (IP), activates p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p38 MAPK inhibition on the cardioprotective effect of IP in the open-chest dogs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in the IP group. p38 MAPK activity markedly increased during IP but did not additionally increase at the onset of ischemia and was even attenuated at 15 minutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphorylated and translocated from cytosol to myofibril or nucleus without affecting total protein level at the onset of ischemia compared with the control group. SB203580 treatment (1 micromol/L) only during IP blunted the infarct size limitation by IP (37.3+/-6.3% versus 7.4+/-2.1% in the IP group, P:<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemic periods had no significant effect on infarct size (33.3+/-9.4%) in this model, treatment with SB203580 only during ischemia partially mimicked the infarct size limitation by IP (26.8+/-3.5%). Thus, transient p38 MAPK activation during ischemic preconditioning mainly mediates the cardioprotection followed by HSP27 phosphorylation and translocation in vivo in the canine heart.
尽管包括缺血预处理（IP）在内的缺血应激会激活p38丝裂原活化蛋白激酶（MAPK），但p38 MAPK激活与IP心脏保护的潜在细胞机制之间的关系尚未在体内得到证实。我们研究了选择性p38 MAPK抑制对开胸犬IP心脏保护作用的影响。冠状动脉闭塞4次，每次5分钟，中间间隔5分钟再灌注（IP），随后再闭塞90分钟，再灌注6小时。我们在IP期间和再灌注1小时、仅在IP期间以及IP组持续缺血期间将SB203580注入冠状动脉。IP期间p38 MAPK活性显著增加，但在缺血开始时没有进一步增加，在持续缺血15分钟时甚至减弱，与对照组相比，热休克蛋白（HSP）27在缺血开始时发生磷酸化并从细胞质转移到肌原纤维或细胞核，而总蛋白水平不受影响。仅在IP期间进行SB203580处理（1 μmol/L）会减弱IP对梗死面积的限制作用（IP组为37.3±6.3%，而处理组为7.4±2.1%，P<0.01），并减弱IP期间HSP27的磷酸化或转移。尽管在整个缺血前期和缺血后期进行SB203580处理对该模型的梗死面积（33.3±9.4%）没有显著影响，但仅在缺血期间用SB203580处理部分模拟了IP对梗死面积的限制作用（26.8±3.5%）。因此，缺血预处理期间短暂的p38 MAPK激活主要介导心脏保护作用，随后在犬心脏体内发生HSP27的磷酸化和转移。
