Ankyrin-B reduction enhances Ca spark-mediated SR Ca release promoting cardiac myocyte arrhythmic activity.
Ankyrin-B reduction enhances Ca spark-mediated SR Ca release promoting cardiac myocyte arrhythmic activity.
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DOI：
10.1016/j.yjmcc.2012.02.010
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发表时间：
2012-06
影响因子：
5
通讯作者：
Despa S
中科院分区：
文献类型：
--
作者：
Camors E;Mohler PJ;Bers DM;Despa S
AnkB功能丧失可导致人类室性心律失常和心脏性猝死。来自AnkB杂合子小鼠（AnkB+/−）的心肌细胞显示Na/Ca交换器（NCX）和Na/K-ATP酶（NKA）的表达减少和定位改变，这两种酶是调节[Na]i和[Ca]i的关键因素。在这里，我们研究AnkB减少如何影响心脏[Na]i，[Ca]i和SR Ca释放。我们发现，与野生型（WT）小鼠相比，AnkB+/−小鼠的肌细胞NCX和NKA转运功能降低，但[Na]i和舒张期[Ca]i不变。在AnkB+/−心肌细胞中，钙瞬变、SR钙含量和SR钙释放分数较大。自发的舒张期钙火花（CaSpF）的频率在来自AnkB+/−的完整肌细胞中显著高于WT肌细胞（有和无异丙肾上腺素），即使在SR钙负荷标准化时。然而，总ryanodine受体（RyR）介导的SR钙泄漏（丁卡因敏感）组间没有差异。因此，在AnkB+/−小鼠中，SR Ca泄漏偏向于更多的Ca火花（相对于较小的释放事件），表明簇中RyR的开放更加协调。这是由于局部胞质RyR调节，而不是内在的RyR差异，因为CaSpF在WT和AnkB+/−小鼠的皂苷透化心肌细胞中相似。更协调的RyRs开放导致AnkB+/−肌细胞中促钙波的倾向增加。总之，AnkB减少改变心脏Na和Ca转运，并增强了耦合RyR开口，导致更频繁的Ca火花和波，虽然总SR Ca泄漏不受影响。这可能会增加AnkB+/−小鼠触发心律失常的倾向。
Ankyrin-B (AnkB) loss-of-function may cause ventricular arrhythmias and sudden cardiac death in humans. Cardiac myocytes from AnkB heterozygous mice (AnkB+/−) show reduced expression and altered localization of Na/Ca exchanger (NCX) and Na/K-ATPase (NKA), key players in regulating [Na]i and [Ca]i. Here we investigate how AnkB reduction affects cardiac [Na]i, [Ca]i and SR Ca release. We found reduced NCX and NKA transport function but unaltered [Na]i and diastolic [Ca]i in myocytes from AnkB+/− vs. wild-type (WT) mice. Ca transients, SR Ca content and fractional SR Ca release were larger in AnkB+/− myocytes. The frequency of spontaneous, diastolic Ca sparks (CaSpF) was significantly higher in intact myocytes from AnkB+/− vs. WT myocytes (with and without isoproterenol), even when normalized for SR Ca load. However, total ryanodine receptor (RyR)-mediated SR Ca leak (tetracaine-sensitive) was not different between groups. Thus, in AnkB+/− mice SR Ca leak is biased towards more Ca sparks (vs. smaller release events), suggesting more coordinated openings of RyRs in a cluster. This is due to local cytosolic RyR regulation, rather than intrinsic RyR differences, since CaSpF was similar in saponin-permeabilized myocytes from WT and AnkB+/− mice. The more coordinated RyRs openings resulted in an increased propensity of pro-arrhythmic Ca waves in AnkB+/− myocytes. In conclusion, AnkB reduction alters cardiac Na and Ca transport and enhances the coupled RyR openings, resulting in more frequent Ca sparks and waves although the total SR Ca leak is unaffected. This could enhance the propensity for triggered arrhythmias in AnkB+/− mice.
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影响因子：
20.1
作者：
Pogwizd, SM;Schlotthauer, K;Bers, DM
通讯作者：
Bers, DM
影响因子：
37.8
作者：
Despa, S;Islam, MA;Bers, DM
通讯作者：
Bers, DM
DOI：
10.1073/pnas.0402546101
发表时间：
2004-06-15
影响因子：
11.1
作者：
Mohler, PJ;Splawski, I;Bennett, V
通讯作者：
Bennett, V
影响因子：
37.8
作者：
Cunha SR;Hund TJ;Hashemi S;Voigt N;Li N;Wright P;Koval O;Li J;Gudmundsson H;Gumina RJ;Karck M;Schott JJ;Probst V;Le Marec H;Anderson ME;Dobrev D;Wehrens XH;Mohler PJ
通讯作者：
Mohler PJ
DOI：
10.1073/pnas.91.8.2965
发表时间：
1994-04-12
影响因子：
11.1
作者：
DEVARAJAN, P;SCARAMUZZINO, DA;MORROW, JS
通讯作者：
MORROW, JS