Loss of the AE3 Cl(-)/HCO(-) 3 exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart.
Loss of the AE3 Cl(-)/HCO(-) 3 exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart.
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DOI：
10.3389/fphys.2013.00399
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发表时间：
2013
影响因子：
4
通讯作者：
Shull GE
中科院分区：
文献类型：
--
作者：
Prasad V;Lorenz JN;Lasko VM;Nieman ML;Al Moamen NJ;Shull GE
Cl−/HCO−3交换器在心肌中大量表达，表明HCO−3的排出在心脏中发挥重要作用。缺乏阴离子交换异构体3（AE 3）（一种主要的心脏Cl−/HCO−3交换体）的小鼠看起来很健康，但AE 3的缺失会导致肥厚型心肌病（HCM）模型的失代偿。使用心室内压力分析，体内起搏和分子研究，我们确定了可能导致HCM失代偿的AE 3丢失引起的生理和生化变化。在基础条件下和β-肾上腺素能刺激后，AE 3基因敲除小鼠的心脏收缩力正常，但心脏起搏显示频率依赖性肌力减弱，这表明在体内急性生物力学应激期间，AE 3介导的HCO−3排出是强大的力-频率反应（FFR）所必需的。观察到影响Ca 2+处理的蛋白质表达的适度变化，但AE 3-null肌细胞的Ca 2+瞬时分析显示正常的抽搐幅度和Ca 2+清除。在起搏的AE 3缺失小鼠的心脏中，与HCM和FFR有关的几种蛋白质的磷酸化和表达，包括受磷蛋白（PLN）、肌球蛋白结合蛋白C和肌钙蛋白I没有改变;然而，在机械感觉信号传导中起中心作用的Akt的磷酸化在起搏的AE 3缺失心脏中显著高于野生型对照，其受Akt影响并参与能量代谢和某些HCM病例。这些数据表明，AE 3的丢失导致心率依赖性变力受损，似乎影响机械应激反应信号传导，并减少AMPK的激活，这可能有助于心力衰竭的失代偿。
Cl−/HCO−3 exchangers are expressed abundantly in cardiac muscle, suggesting that HCO−3 extrusion serves an important function in heart. Mice lacking Anion Exchanger Isoform 3 (AE3), a major cardiac Cl−/HCO−3 exchanger, appear healthy, but loss of AE3 causes decompensation in a hypertrophic cardiomyopathy (HCM) model. Using intra-ventricular pressure analysis, in vivo pacing, and molecular studies we identified physiological and biochemical changes caused by loss of AE3 that may contribute to decompensation in HCM. AE3-null mice had normal cardiac contractility under basal conditions and after β-adrenergic stimulation, but pacing of hearts revealed that frequency-dependent inotropy was blunted, suggesting that AE3-mediated HCO−3 extrusion is required for a robust force-frequency response (FFR) during acute biomechanical stress in vivo. Modest changes in expression of proteins that affect Ca2+-handling were observed, but Ca2+-transient analysis of AE3-null myocytes showed normal twitch-amplitude and Ca2+-clearance. Phosphorylation and expression of several proteins implicated in HCM and FFR, including phospholamban (PLN), myosin binding protein C, and troponin I were not altered in hearts of paced AE3-null mice; however, phosphorylation of Akt, which plays a central role in mechanosensory signaling, was significantly higher in paced AE3-null hearts than in wild-type controls and phosphorylation of AMPK, which is affected by Akt and is involved in energy metabolism and some cases of HCM, was reduced. These data show loss of AE3 leads to impaired rate-dependent inotropy, appears to affect mechanical stress-responsive signaling, and reduces activation of AMPK, which may contribute to decompensation in heart failure.
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影响因子：
10.5
作者：
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通讯作者：
Rottbauer, Wolfgang
影响因子：
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作者：
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DOI：
10.1073/pnas.94.15.8121
发表时间：
1997-07-22
影响因子：
11.1
作者：
DAngelo, DD;Sakata, Y;Dorn, GW
通讯作者：
Dorn, GW
DOI：
10.1152/ajpheart.00449.2006
发表时间：
2007-03-01
影响因子：
4.8
作者：
Alvarez, Bernardo V.;Kieller, Dawn M.;Casey, Joseph R.
通讯作者：
Casey, Joseph R.