Dual actions of the Galpha(q) agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility.
Dual actions of the Galpha(q) agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility.
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Galpha(q) 激动剂多杀性巴斯德氏菌毒素具有促进心肌细胞肥大和增强细胞凋亡易感性的双重作用。
DOI：
10.1161/01.res.0000016165.23795.1f
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发表时间：
2002
影响因子：
20.1
通讯作者：
Steinberg,SusanF
中科院分区：
文献类型：
--
作者：
Sabri,Abdelkarim;Wilson,BrendaA;Steinberg,SusanF
以前试图描述心肌细胞中Gα q激活的结果主要依赖于培养物或转基因小鼠中的分子策略。适度水平的野生型Gα q过表达诱导稳定的心肌肥大，而强烈的Gα q刺激诱导心肌细胞凋亡。诱导心肌肥大的Gα q亚基的传统靶点也触发心肌细胞凋亡的确切机制尚不清楚，用重组多杀性巴氏杆菌毒素（rPMT，一种Gα q激动剂）进行了探索。与rPMT一起培养的细胞显示心肌细胞增大、肌节组织化和增加的心房利钠因子表达，其与磷脂酶C、新型蛋白激酶C（PKC）亚型、细胞外信号调节蛋白激酶（ERK）和（在较小程度上）JNK/p38-MAPK的活化相关。rPMT通过表皮生长因子（EGF）受体反式激活心脏成纤维细胞中的ERK级联，但EGF受体反式激活在心肌细胞中的ERK激活中不起作用。令人惊讶的是，rPMT（或新的PKC亚型激活PMA）减少基础Akt磷酸化; rPMT防止Akt磷酸化EGF或IGF-1和功能增强心肌细胞凋亡响应H2 O2。这些结果确定了Gαq-PKC通路，其抑制基础Akt磷酸化并通过存活因子损害Akt刺激。由于Akt的抑制增强了心肌细胞对凋亡的易感性，因此预测该途径有助于从肥大向心脏失代偿的转变，并且可以靶向治疗心力衰竭。
Previous attempts to delineate the consequences of Gαqactivation in cardiomyocytes relied largely on molecular strategies in cultures or transgenic mice. Modest levels of wild-type Gαqoverexpression induce stable cardiac hypertrophy, whereas intense Gαqstimulation induces cardiomyocyte apoptosis. The precise mechanism(s) whereby traditional targets of Gαqsubunits that induce hypertrophy also trigger cardiomyocyte apoptosis is not obvious and is explored with recombinantPasteurella multocidatoxin (rPMT, a Gαqagonist). Cells cultured with rPMT display cardiomyocyte enlargement, sarcomeric organization, and increased atrial natriuretic factor expression in association with activation of phospholipase C, novel protein kinase C (PKC) isoforms, extracellular signal-regulated protein kinase (ERK), and (to a lesser extent) JNK/p38-MAPK. rPMT stimulates the ERK cascade via epidermal growth factor (EGF) receptor transactivation in cardiac fibroblasts, but EGF receptor transactivation plays no role in ERK activation in cardiomyocytes. Surprisingly, rPMT (or novel PKC isoform activation by PMA) decreases basal Akt phosphorylation; rPMT prevents Akt phosphorylation by EGF or IGF-1 and functionally augments cardiomyocyte apoptosis in response to H2O2. These results identify a Gαq-PKC pathway that represses basal Akt phosphorylation and impairs Akt stimulation by survival factors. Because inhibition of Akt enhances cardiomyocyte susceptibility to apoptosis, this pathway is predicted to contribute to the transition from hypertrophy to cardiac decompensation and could be targeted for therapy in heart failure.