Marais E, Genade S, Strijdom H, Moolman J A, Lochner A
Department of Medical Physiology, University of Stellenbosch Faculty of Health Sciences, Tygerberg, Republic of South Africa.
J Mol Cell Cardiol. 2001 Dec;33(12):2157-77. doi: 10.1006/jmcc.2001.1478.
p38 Mitogen-activated protein kinase (p38 MAPK) is activated by short episodes of ischaemia-reperfusion as well as by sustained ischemia followed by reperfusion, Whether activation of this kinase is beneficial or deleterious to the ischaemic heart is still a subject of controversy. Since transient beta-adrenergic stimulation (5 min) stimulates p38 MAPK activation and mimics the cardioprotection of ischaemic preconditioning, it was used as a tool to further evaluate the role of this kinase in cardioprotection. The isolated perfused working rat heart, subjected to 25 min ischaemia and 30 min reperfusion was used as experimental model. p38 MAPK and ATF2 activation was determined using Western blots. The results showed that isoproterenol stimulated p38 MAPK in a dose- and time-dependent manner. Ischaemia-induced activation of p38 MAPK could be partially abolished by beta- and alpha1-adrenergic receptor blockade. Isoproterenol activation of the kinase could be abolished by alprenolol and verapamil, but not by 8-cyclopentyladenosine. p38 MAPK activation induced by either a multi-episode preconditioning protocol or isoproterenol (10(-7) M for 5 min) was associated with a significant reduction in p38 MAPK activation at all time intervals studied during 25 min global ischaemia and at 20 and 30 min of reperfusion, compared with the marked activation observed in untreated non-preconditioned hearts. In each case attenuation of p38 MAPK activation during ischaemia and during reperfusion was associated with improved functional recovery during reperfusion. Cyclic elevations in tissue cAMP during an ischaemic preconditioning protocol acted as trigger of cardioprotection, since pretreatment of such hearts with alprenolol abolished cardioprotection. Mechanical failure in such hearts was characterized by a significant stimulation of p38 MAPK activity during ischaemia and reperfusion. However, p38 MAPK activation during an ischaemic preconditioning protocol did not act as trigger: inhibition of p38 MAPK activation by SB 203580 during the preconditioning phase did not abolish cardioprotection. In fact, functional recovery was significantly better than that of untreated preconditioned hearts. On the other hand, SB 203580, when administered before and during the isoproterenol-preconditioning protocol abolished cardioprotection, suggesting that p38 MAPK activation by a beta -adrenergic-induced preconditioning protocol does act as trigger of cardioprotection. In addition, attenuation of p38 MAPK activity during sustained ischaemia and reperfusion as occurs in ischaemic- or isoproterenol-preconditioned hearts, is beneficial.
p38丝裂原活化蛋白激酶（p38 MAPK）可被短暂的缺血再灌注激活，也可被持续性缺血后继以再灌注激活。这种激酶的激活对缺血心脏是有益还是有害，仍是一个有争议的问题。由于短暂的β-肾上腺素能刺激（5分钟）可刺激p38 MAPK激活，并模拟缺血预处理的心脏保护作用，因此它被用作进一步评估该激酶在心脏保护中作用的工具。以离体灌注的工作大鼠心脏为实验模型，使其经历25分钟缺血和30分钟再灌注。使用蛋白质免疫印迹法测定p38 MAPK和活化转录因子2（ATF2）的激活情况。结果表明，异丙肾上腺素以剂量和时间依赖性方式刺激p38 MAPK。缺血诱导的p38 MAPK激活可被β-和α1-肾上腺素能受体阻断部分消除。该激酶的异丙肾上腺素激活可被阿普洛尔和维拉帕米消除，但不能被8-环戊基腺苷消除。多阶段预处理方案或异丙肾上腺素（10⁻⁷ M，5分钟）诱导的p38 MAPK激活，与在25分钟全心缺血期间以及再灌注20和30分钟时所有研究时间间隔内p۳8 MAPK激活的显著降低相关，与未处理的非预处理心脏中观察到的明显激活相比。在每种情况下，缺血期间和再灌注期间p38 MAPK激活的减弱都与再灌注期间功能恢复的改善相关。缺血预处理方案期间组织环磷酸腺苷（cAMP）的周期性升高是心脏保护的触发因素，因为用阿普洛尔预处理此类心脏可消除心脏保护作用。此类心脏的机械功能衰竭的特征是缺血和再灌注期间p38 MAPK活性受到显著刺激。然而，缺血预处理方案期间p38 MAPK的激活并非触发因素：在预处理阶段用SB 203580抑制p38 MAPK激活并不能消除心脏保护作用。事实上，功能恢复明显优于未处理的预处理心脏。另一方面，在异丙肾上腺素预处理方案之前和期间给予SB 203580可消除心脏保护作用这表明β-肾上腺素能诱导的预处理方案激活p38 MAPK确实是心脏保护的触发因素。此外，在缺血或异丙肾上腺素预处理的心脏中发生的持续性缺血和再灌注期间p38 MAPK活性的减弱是有益的。
