A transgenic mouse model of heart failure using inducible Gαq
A transgenic mouse model of heart failure using inducible Gαq
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DOI：
10.1074/jbc.m506810200
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发表时间：
2005-12-02
影响因子：
4.8
通讯作者：
Lin, RZ
中科院分区：
文献类型：
--
作者：
Fan, GF;Jiang, YP;Lin, RZ
与G α（q）偶联的受体在心力衰竭的发展中起关键作用。使用转基因小鼠的研究表明，G alpha（q）介导心肌细胞的肥大反应。在这些模型中，G alpha（q）信号在早期生长和发育过程中被修改，而大多数人类心力衰竭发生在成年期心脏损伤后。为了确定仅在成年时表达增加的G α（q）信号传导的动物的表型，我们产生了在心肌细胞中表达沉默的G α（q）蛋白（G α（q）Q209 L-hbER）的转基因小鼠，其可以被他莫昔芬激活。在药物治疗以激活G α（q）Q209 L-hbER后，这些小鼠迅速发展为扩张型心肌病和心力衰竭。这种表型似乎不涉及心肌细胞肥大，但与受磷蛋白（PLB）的去磷酸化，肌浆网Ca 2 +-ATP酶活性降低，L型Ca 2+电流密度降低有关。在（G α（q）Q209 L-hbER）激活后1周，Ca 2+处理的变化和心肌收缩力的降低是明显的。相比之下，表达不能激活磷脂酶C β（PLC β）的诱导型G α（q）突变体的转基因小鼠不会发生心力衰竭或PLB磷酸化的变化，但确实显示出L型Ca 2+电流密度降低。这些结果表明，成年小鼠心肌细胞中G α（q）的激活导致需要PLC激活的扩张型心肌病。然而，增加PLC β信号不是所有G α（q）诱导的心脏异常所必需的。
Receptors coupled to G alpha(q) play a key role in the development of heart failure. Studies using genetically modified mice suggest that G alpha(q) mediates a hypertrophic response in cardiac myocytes. G alpha(q) signaling in these models is modified during early growth and development, whereas most heart failure in humans occurs after cardiac damage sustained during adulthood. To determine the phenotype of animals that express increased G alpha(q) signaling only as adults, we generated transgenic mice that express a silent G alpha(q) protein (G alpha(q) Q209L- hbER) in cardiac myocytes that can be activated by tamoxifen. Following drug treatment to activate G alpha(q)Q209L- hbER, these mice rapidly develop a dilated cardiomyopathy and heart failure. This phenotype does not appear to involve myocyte hypertrophy but is associated with dephosphorylation of phospholamban ( PLB), decreased sarcoplasmic reticulum Ca2+- ATPase activity, and a decrease in L-type Ca2+ current density. Changes in Ca2+ handling and decreased cardiac contractility are apparent 1 week after (G alpha(q) Q209L-hbER) activation. In contrast, transgenic mice that express an inducible G alpha(q) mutant that cannot activate phospholipase C beta (PLC beta) do not develop heart failure or changes in PLB phosphorylation, but do show decreased L-type Ca2+ current density. These results demonstrate that activation of G alpha(q) in cardiac myocytes of adult mice causes a dilated cardiomyopathy that requires the activation of PLC . However, increased PLC beta signaling is not required for all of the G alpha(q)-induced cardiac abnormalities.