Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model.
Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model.
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RyR2-R176Q 敲入小鼠模型中压力过载诱导的心脏肥大和功能障碍的加速发展。
DOI：
10.1161/hypertensionaha.109.146449
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Wehrens XH
中科院分区：
文献类型：
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作者：
van Oort RJ;Respress JL;Li N;Reynolds C;De Almeida AC;Skapura DG;De Windt LJ;Wehrens XH
为了应对慢性高血压，心脏通过肥大性生长进行代偿，这常常进展为心力衰竭。尽管 Ca2+ 在肥大信号通路中发挥核心作用，但激活这些通路的 Ca2+ 来源仍然难以捉摸。我们假设病理性肌浆网 Ca2+ 通过有缺陷的心脏细胞内 Ca2+ 释放通道/兰尼碱受体 (RyR2) 渗漏，通过刺激 Ca2+ 依赖性肥大信号传导加速心力衰竭的发展。对 RyR2 中功能获得性突变 R176Q/+ 杂合的小鼠和野生型 (WT) 小鼠进行横向主动脉缩窄 (TAC)。与 WT 小鼠相比，TAC 后 8 周，R176Q/+ 小鼠的心脏功能显着降低，心脏尺寸更大。根据 TAC 后心脏重量与体重比和心肌细胞横截面积的评估，与 WT 小鼠相比，R176Q/+ 小鼠表现出增强的肥大反应。定量 PCR 显示 TAC 后 R176Q/+ 小鼠心脏应激基因的转录激活增加。此外，与WT相比，压力超负荷导致R176Q/+小鼠中SR Ca2+渗漏增加，与钙调神经磷酸酶-1（RCAN1-4）调节剂的外显子4剪接形式的较高表达水平相关，以及活化T细胞核因子（NFAT）磷酸化的减少。综上所述，我们的结果表明，RyR2 依赖性 SR Ca2+ 渗漏在压力超负荷条件下激活促肥大性钙调神经磷酸酶/NFAT 途径。
In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although Ca2+ has a central role in hypertrophic signaling pathways, the Ca2+ source for activating these pathways remains elusive. We hypothesized that pathological sarcoplasmic reticulum Ca2+ leak through defective cardiac intracellular Ca2+ release channels/ ryanodine receptors (RyR2) accelerates heart failure development by stimulating Ca2+-dependent hypertrophic signaling. Mice heterozygous for the gain-of-function mutation R176Q/+ in RyR2 and wildtype (WT) mice were subjected to transverse aortic constriction (TAC). Cardiac function was significantly lower, and cardiac dimensions were larger at 8 weeks after TAC in R176Q/+ compared with WT mice. R176Q/+ mice displayed an enhanced hypertrophic response compared to WT mice as assessed by heart weight to body weight ratios and cardiomyocyte cross sectional areas after TAC. Quantitative PCR revealed increased transcriptional activation of cardiac stress genes in R176Q/+ mice after TAC. Moreover, pressure overload resulted in an increased SR Ca2+ leak, associated with higher expression levels of the exon 4 splice form of regulator of calcineurin-1 (RCAN1-4), and a decrease in nuclear factor of activated T-cells (NFAT) phosphorylation in R176Q/+ mice compared to WT. Taken together, our results suggest that RyR2-dependent SR Ca2+ leak activates the pro-hypertrophic calcineurin/NFAT pathway under conditions of pressure overload.