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

本研究探讨了缺血时心肌间隙连接（GJ）通透性改变与心肌坏死的关系及缺血预处理（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，缺血30分钟后检测到显著的去磷酸化，并且这种去磷酸化通过抑制蛋白激酶C（PKC）而被抑制。PC诱导PKC-ε向闰盘移位，并显著加速缺血诱导的Cx43去磷酸化。在心肌缺血过程中GJ渗透性的减少同样加速PC和GJ阻滞剂，庚醇。三种结构不同的GJ阻断剂（庚醇、2，3-丁二酮单肟、18β-大黄酸）在缺血开始后输注，限制了30 min缺血/2 h再灌注后的梗死范围，其心脏保护作用与PC相当。这些结果表明，GJ是缺血/再灌注期间心肌坏死的决定因素，PC可能通过PKC介导的Cx43去磷酸化加速缺血期间GJ闭合，从而导致心脏保护。

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.