Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart
Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart
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DOI：
10.1152/ajpheart.00082.2004
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发表时间：
2004-09-01
影响因子：
4.8
通讯作者：
Boyden, PA
中科院分区：
文献类型：
--
作者：
Dun, W;Baba, SG;Boyden, PA
心肌梗死后第5天的心外膜边界区(EBZ)细胞的动作电位(AP)在缺血后第14天继续发生改变，即缩短。然而，到2个月时，EBZ AP看起来“正常”，但波前传导仍然异常。我们假设跨膜AP的改变是由于离子通道在密度或功能上的分布的改变。因此，我们重点研究了从14天(IZ(14d))和2-mo(IZ(2m))EBZ分离的细胞中钙和钾电流的变化，并将它们与来自同一心脏但远离EBZ(Rem)的细胞的变化进行了比较。采用全细胞电压钳技术测量和比较不同组别细胞的钙、钾电流。在14天和2个月的心肌梗死后，细胞内的钙电流密度仍然降低，而之前在5天的心脏中发现的动力学变化开始从非梗死区的心外膜(NZ)值恢复到细胞。重要的是，EBZ和REM区的I-Ca、I-L仍显示出从失活状态恢复的缓慢。此外，在重构过程中，T型钙电流的表达增加，但仅限于局部，且仅在心肌梗死后特定的时间窗内表达。心肌细胞β-肾上腺素能反应性的区域异质性，I-L存在于14天心脏的EBZ和远隔细胞之间，但在愈合的梗塞心脏中这种区域异质性消失了。在IZ(14d)，瞬时外向钾电流(I-to)开始重新出现，并伴随着上调的四乙基铵敏感外向电流。结扎后2mo，I-to和持续外向K+电流已完成反向重构过程。在心肌梗塞后的修复过程中，犬心外膜细胞下调快速I-to，但通过上调正常细胞最低功能的K+电流来进行补偿。在恢复14天和2-mo EBZ细胞的I-Ca，I-L的过程中，电压依赖性过程似乎被重置，使I-Ca，I-L“窗”电流出现在超极化电位。因此，钙和钾电流的动态变化有助于在14天的纤维中观察到AP的改变，并可能解释2个月EBZ纤维的AP的返回。
Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 infarcted heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs appear "normal," yet conduction of wave fronts remains abnormal. We hypothesize that the changes in transmembrane APs are due to a change in the distribution of ion channels in either density or function. Thus we focused on the changes in Ca2+ and K+ currents in cells isolated from the 14-day (IZ(14d)) and 2-mo ( IZ(2m)) EBZ and compared them with those occurring in cells from the same hearts but remote ( Rem) from the EBZ. Whole cell voltage-clamp techniques were used to measure and compare Ca2+ and K+ currents in cells from the different groups. Ca2+ current densities remain reduced in cells of the 14-day and 2-mo infarcted heart and the kinetic changes previously identified in the 5-day heart begin to, but do not recover to, cells from noninfarcted epicardium (NZ) values. Importantly, I-Ca,I-L in both the EBZ and Rem regions still show a slowed recovery from inactivation. Furthermore, during the remodeling process, there is an increased expression of T-type Ca2+ currents, but only regionally, and only within a specific time window postmyocardial infarction (MI). Regional heterogeneity in beta-adrenergic responsiveness of I-Ca,I-L exists between EBZ and remote cells of the 14-day hearts, but this regional heterogeneity is gone in the healed infarcted heart. In IZ(14d), the transient outward K+ current (I-to) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, I-to and sustained outward K+ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast I-to but compensate by upregulating a K+ current that in normal cells is minimally functional. For recovering I-Ca,I-L of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that I-Ca,I-L "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca2+ and K+ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.