Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice.
Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice.
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发表时间：
2005
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通讯作者：
P. Zhai;Mitsutaka Yamamoto;Jonathan P. Galeotti;Jing Liu;M. Masurekar;Jill Thaisz;Keiichi Irie;E. Holle;Xianzhong Yu;S. Kupershmidt;D. Roden;T. Wagner;A. Yatani;D. Vatner;S. Vatner;J. Sadoshima
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作者：
P. Zhai;Mitsutaka Yamamoto;Jonathan P. Galeotti;Jing Liu;M. Masurekar;Jill Thaisz;Keiichi Irie;E. Holle;Xianzhong Yu;S. Kupershmidt;D. Roden;T. Wagner;A. Yatani;D. Vatner;S. Vatner;J. Sadoshima
血管紧张素II 1型（AT1）受体激活常规的异源三聚体G蛋白依赖机制和非传统的G蛋白非依赖机制。我们研究了AT1受体激活的这些不同机制如何影响体内心肌细胞的生长和死亡。对心脏特异性过表达野生型AT1受体（AT1 - WT；Tg - WT小鼠）或选择性激活Gαq/Gαi非依赖机制的AT1受体第二个细胞内环突变体（AT1 - i2m；Tg - i2m小鼠）的转基因小鼠进行了研究。Tg - i2m小鼠比Tg - WT小鼠出现更严重的心肌肥大和心动过缓，且心脏功能更低。相反，Tg - WT小鼠比Tg - i2m小鼠表现出更严重的纤维化和细胞凋亡。与Tg - WT小鼠相比，慢性血管紧张素II输注在Tg - i2m小鼠中诱导更严重的心肌肥大，而急性血管紧张素II给药使Tg - WT小鼠心率增加，但Tg - i2m小鼠心率无增加。仅在Tg - WT小鼠中观察到PKCε的膜转位、Gαq的胞质转位和磷酸化 - ERKs的核定位，而在Tg - i2m小鼠中Src的激活和磷酸化 - ERKs的胞质积累更显著，这与Tg - i2m小鼠中Gαq/Gαi非依赖机制被激活的观点一致。与表达AT1 - WT的细胞相比，表达AT1 - i2m的培养心肌细胞在肥大方面的血管紧张素II剂量 - 反应曲线向左上移位。因此，AT1受体通过Gαq/Gαi依赖和非依赖机制介导下游信号传导机制，这些机制诱导具有不同表型的肥大。
Ang II type 1 (AT1) receptors activate both conventional heterotrimeric G protein-dependent and unconventional G protein-independent mechanisms. We investigated how these different mechanisms activated by AT1 receptors affect growth and death of cardiac myocytes in vivo. Transgenic mice with cardiac-specific overexpression of WT AT1 receptor (AT1-WT; Tg-WT mice) or an AT1 receptor second intracellular loop mutant (AT1-i2m; Tg-i2m mice) selectively activating G(alpha)q/G(alpha)i-independent mechanisms were studied. Tg-i2m mice developed more severe cardiac hypertrophy and bradycardia coupled with lower cardiac function than Tg-WT mice. In contrast, Tg-WT mice exhibited more severe fibrosis and apoptosis than Tg-i2m mice. Chronic Ang II infusion induced greater cardiac hypertrophy in Tg-i2m compared with Tg-WT mice whereas acute Ang II administration caused an increase in heart rate in Tg-WT but not in Tg-i2m mice. Membrane translocation of PKCepsilon, cytoplasmic translocation of G(alpha)q, and nuclear localization of phospho-ERKs were observed only in Tg-WT mice while activation of Src and cytoplasmic accumulation of phospho-ERKs were greater in Tg-i2m mice, consistent with the notion that G(alpha)q/G(alpha)i-independent mechanisms are activated in Tg-i2m mice. Cultured myocytes expressing AT1-i2m exhibited a left and upward shift of the Ang II dose-response curve of hypertrophy compared with those expressing AT1-WT. Thus, the AT1 receptor mediates downstream signaling mechanisms through G(alpha)q/G(alpha)i-dependent and -independent mechanisms, which induce hypertrophy with a distinct phenotype.