Modification of gap junctions during myocardial ischemia and its significance in myocardial necrosis

在本研究中，我们评估了1)缺血时缝隙连接(GJ)通透性改变与心肌坏死的关系以及2)缺血预适应(PC)对缝隙连接蛋白43(Cx43)和GJ功能的影响。在兔心肌缺血模型中，在缺血30min后检测到显著的去磷酸化，这种去磷酸化可被蛋白激酶C(PKC)抑制。PC可诱导PKC-ε移位至间盘，并显著加速缺血诱导的Cx43去磷酸化。心肌缺血时GJ通透性的降低同样被PC和GJ阻滞剂庚醇加速。3种结构不同的GJ阻滞剂(庚醇、2，3-丁二酮单肟、18β-甘草次酸)在缺血30min/再灌流2小时后输注，其心肌保护作用与PC相当。这些结果提示GJ是缺血/再灌注期心肌坏死的决定因素，PC可能通过PKC介导的Cx43去磷酸化促进缺血时GJ的关闭，从而起到心脏保护作用。

In the present study, we assessed 1) relationship between alteration of gap junction (GJ) permeability and myocardial necrosis during ischemia and 2) effects of ischemic preconditioning (PC) on connexin43 (Cx43) and GJ function. Significant dephosphorylation was detected after 30 min of ischemia, and this dephosphorylation was suppressed by inhibition of protein kinase C (PKC) in a rabbit model of myocardial ischemia. PC induced translocation of PKC-ε to the intercalated disk and significantly accelerated this ischemia-induced Cx43 dephosphorylation. Reduction in GJ permeability during myocardial ischemia was similarly accelerated by PC and a GJ blocker, heptanol. Three structurally different GJ blockers (heptanol, 2,3-butanedione monoxime, 18β-glycyrrhetinic acid) that were infused after the onset of ischemia limited infarct size after 30-min ischemia/2-h reperfusion, and their cardioprotective effects were equivalent to PC. These results suggest that GJ is a determinant of myocardial necrosis during ischemia/reperfusion and that PC accelerates GJ closure during ischemia possibly by PKC-mediated Cx43 dephosphorylation, leading to cardioprotection.