Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy.
Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy.
复制标题
作者：
Brewster AL;Marzec K;Hairston A;Ho M;Anderson AE;Lai YC
癫痫持续状态(SE)与多种急性和慢性心脏改变有关，包括交感神经张力增加、节律和心室复极障碍。尽管有这些观察，但SE相关心肌重塑背后的分子过程仍有待确定。在这里，我们使用SE和获得性癫痫的模型来确定SE相关的早期心肌电学和分子改变。我们在红藻氨酸诱发SE后2周开始对大鼠进行心电图(CG)评估，并计算校正QT间期(QTC)的短期变异性(STV)作为心室稳定性的标志。用免疫印迹法检测心肌β1肾上腺素能受体(β1 AR)和心室缝隙连接蛋白43(Cx43)水平，以此作为交感神经张力增加的指标。我们确定了三种与交感神经刺激相关的激酶及其下游离子通道靶点的激活状态：细胞外信号调节激酶(ERK)、蛋白激酶A(PKA)、钙/钙调素依赖的蛋白激酶II(CaMKII)、超极化激活的环核苷酸门控通道亚单位2(HCN2)和电压门控钾通道4.2(Kv4.2)。我们通过Western blotting检测特定的钙处理蛋白水平，研究了SE是否与钙稳态改变有关。与假手术组相比，SE组动物在SE后2周开始表现出更高的心率、更长的QTC间期和更高的STV。同时，SE大鼠心肌表现为β1-AR降低，Cx43蛋白水平升高，磷酸化的ERK1-AR、PKA和CaMKII水平升高，Hcn2和Kv4.2通道水平降低。此外，SE大鼠还改变了钙处理蛋白的蛋白水平，降低了Na+/Ca2+交换器-1，增加了钙网蛋白。硒在心肌中引发早期分子改变，与交感神经张力增加和钙稳态改变一致。这些变化，加上早期和持续的心电图异常，表明所观察到的分子变化可能有助于SE相关的心脏重构。还需要更多的机制研究来确定潜在的因果作用。
A myriad of acute and chronic cardiac alterations are associated with status epilepticus (SE) including increased sympathetic tone, rhythm and ventricular repolarization disturbances. Despite these observations, the molecular processes underlying SE-associated myocardial remodeling remain to be identified. Here we determined early SE-associated myocardial electrical and molecular alterations using a model of SE and acquired epilepsy. We performed electrocardiography (ECG) assessments in rats beginning at 2 weeks following kainate-induced SE, and calculated short-term variability (STV) of the corrected QT intervals (QTc) as a marker of ventricular stability. Using western blotting, we quantified myocardial β1-adrenergic receptors (β1-AR) and ventricular gap junction protein connexin 43 (Cx43) levels as makers of increased sympathetic tone. We determined the activation status of three kinases associated with sympathetic stimulation and their downstream ion channel targets: extracellular signal-regulated kinase (ERK), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CamKII), hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2), and voltage-gated potassium channels 4.2 (Kv4.2). We investigated whether SE was associated with altered Ca2+ homeostasis by determining select Ca2+-handling protein levels using western blotting. Compared with the sham group, SE animals exhibited higher heart rate, longer QTc interval, and higher STV beginning at 2 weeks following SE. Concurrently, the myocardium of SE rats showed lower β1-AR and higher Cx43 protein levels, higher levels of phosphorylated ERK, PKA, and CamKII along with decreased HCN2 and Kv4.2 channel levels. In addition, the SE rats had altered proteins levels of Ca2+-handling proteins, with decreased Na+/Ca2+ exchanger-1 and increased calreticulin. SE triggers early molecular alterations in the myocardium consistent with increased sympathetic tone and altered Ca2+ homeostasis. These changes, coupled with early and persistent ECG abnormalities, suggest that the observed molecular alterations may contribute to SE-associated cardiac remodeling. Additional mechanistic studies are needed to determine potential causal roles.
登录
查看更多内容
影响因子：
2.2
作者：
Bealer, Steven L.;Little, Jason G.;Metcalf, Cameron S.;Brewster, Amy L.;Anderson, Anne E.
通讯作者：
Anderson, Anne E.
钙网蛋白结构域的功能专业化。
影响因子：
7.8
作者：
Nakamura, K;Zuppini, A;Arnaudeau, S;Lynch, J;Ahsan, I;Krause, R;Papp, S;De Smedt, H;Parys, J B;Muller-Esterl, W;Lew, D P;Krause, K H;Demaurex, N;Opas, M;Michalak, M
通讯作者：
Michalak, M
影响因子：
20.1
作者：
Luo M;Anderson ME
通讯作者：
Anderson ME
影响因子：
56.9
作者：
Bernard, C;Anderson, A;Johnston, D
通讯作者：
Johnston, D
影响因子：
5.6
作者：
Metcalf, Cameron S.;Radwanski, Przemyslaw B.;Bealer, Steven L.
通讯作者：
Bealer, Steven L.