Mechanism of enhanced cardiac function in mice with hypertrophy induced by overexpressed Akt
Mechanism of enhanced cardiac function in mice with hypertrophy induced by overexpressed Akt
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DOI：
10.1074/jbc.m305909200
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发表时间：
2003-11-28
影响因子：
4.8
通讯作者：
Vatner, SF
中科院分区：
文献类型：
--
作者：
Kim, YK;Kim, SJ;Vatner, SF
心脏特异性过表达活性Akt（TG）的转基因小鼠不仅表现出肥大，而且表现出增强的左心室（LV）功能。在3-4月龄的TG中，与非转基因同窝出生的动物（野生型（WT））（73 ± 1%）相比，心脏/体重增加60%，LV射血分数升高（84 +/-2%，p < 0.01）。与WT相比，TG中分离的心室肌细胞收缩功能（%收缩）的增加（6.1 ± 0.2 vs 3.5 ± 0.2%，p < 0.01）与Fura-2 Ca 2+瞬变增加（396 +/- 50 vs 250 +/- 24 nmol/L，p < 0.05）相关。TG的舒张速率（+dL/dt）也增加（214 ± 15对98 ± 18 μm/s，p < 0.01）。与WT相比，TG中的L-型Ca 2+电流（I-Ca）密度增加（-9.0 +/-0.3对7.2 +/-0.3 pA/pF，p < 0.01）。肌浆网Ca ~（2+）ATP酶2a（SERCA 2a）蛋白水平在TG中增加了6.6倍（p < 0.05），这可以通过腺病毒介导的Akt在培养的成人心室肌细胞中的过表达在体外重现。相反，抑制SERCA与ryanodine或毒胡萝卜素影响心肌细胞收缩和舒张和Ca 2+通道动力学TG比WT。因此，Akt过表达小鼠的肌细胞表现出增强的收缩性和舒张性、Fura-2 Ca 2+瞬变和Ca 2+通道电流。此外，SERCA 2a蛋白表达的增加在介导Akt增强的LV功能中起重要作用。在Akt诱导的肥大中SERCA 2a表达的上调和增强的LV肌细胞收缩和舒张与在许多其他形式的LV肥大中观察到的SERCA 2a下调和收缩功能降低相反。
Transgenic mice with cardiac-specific overexpression of active Akt (TG) not only exhibit hypertrophy but also show enhanced left ventricular (LV) function. In 3-4-month-old TG, heart/body weight was increased by 60% and LV ejection fraction was elevated (84 +/- 2%, p < 0.01) compared with nontransgenic littermates ( wild type (WT)) (73 ± 1%). An increase in isolated ventricular myocyte contractile function (% contraction) in TG compared with WT (6.1 ± 0.2 versus 3.5 ± 0.2%, p < 0.01) was associated with increased Fura-2 Ca2+ transients (396 +/- 50 versus 250 +/- 24 nmol/liter, p < 0.05). The rate of relaxation (+dL/dt) was also enhanced in TG (214 ± 15 versus 98 ± 18 μm/s, p < 0.01). L-type Ca2+ current (I-Ca) density was increased in TG compared with WT (-9.0 +/- 0.3 versus 7.2 +/- 0.3 pA/pF, p < 0.01). Sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein levels were increased (p < 0.05) by 6.6-fold in TG, which could be recapitulated in vitro by adenovirus-mediated overexpression of Akt in cultured adult ventricular myocytes. Conversely, inhibiting SERCA with either ryanodine or thapsigargin affected myocyte contraction and relaxation and Ca2+ channel kinetics more in TG than in WT. Thus, myocytes from mice with overexpressed Akt demonstrated enhanced contractility and relaxation, Fura-2 Ca2+ transients, and Ca2+ channel currents. Furthermore, increased protein expression of SERCA2a plays an important role in mediating enhanced LV function by Akt. Up-regulation of SERCA2a expression and enhanced LV myocyte contraction and relaxation in Akt-induced hypertrophy is opposite to the down-regulation of SERCA2a and reduced contractile function observed in many other forms of LV hypertrophy.