Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction
Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction
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DOI：
10.1074/jbc.m109.057273
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发表时间：
2009-12-18
影响因子：
4.8
通讯作者：
Walsh, Kenneth
中科院分区：
文献类型：
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作者：
Ikeda, Yasumasa;Sato, Kaori;Walsh, Kenneth
LKB 1编码丝氨酸/苏氨酸激酶，其在AMP活化蛋白激酶（AMPK）超家族的上游起作用。为了阐明LKB 1在心脏中的作用，我们使用α-肌球蛋白重链-Cre缺失株产生并表征心肌细胞特异性LKB 1敲除（KO）小鼠。LKB 1-KO小鼠在4周龄时表现出双心房扩大伴房颤和心功能障碍。在LKB 1-KO小鼠12周龄时观察到左心室肥大，但在4周龄时未观察到。4周时，心房I型和III型胶原mRNA表达升高，12周时可见心房纤维化。LKB 1-KO小鼠表现出心脏功能障碍和心房纤颤，并在6个月龄内死亡。在LKB 1缺陷小鼠的心房和心室中，AMPK和eEF 2的磷酸化减少，而哺乳动物雷帕霉素靶蛋白（mTOR）磷酸化和p70 S6激酶磷酸化增加，这表明存在促肥大环境。与LKB 1-KO小鼠中血管内皮生长因子mRNA和蛋白水平显著降低一致，这些小鼠还表现出心房和心室的毛细血管密度降低。在培养的心肌细胞中，LKB 1沉默诱导肥大，这是通过表达组成型活性形式AMPK或通过用mTOR抑制剂雷帕霉素治疗来改善的。这些发现表明，心肌细胞中的LKB 1信号传导对于心房和心室的正常发育至关重要。LKB 1缺陷心脏的心脏肥大和功能障碍与AMPK和mTOR/p70 S6激酶/eEF 2信号传导的改变以及血管内皮生长因子表达和血管稀疏的减少有关。
LKB1 encodes a serine/threonine kinase, which functions upstream of the AMP-activated protein kinase (AMPK) superfamily. To clarify the role of LKB1 in heart, we generated and characterized cardiac myocyte-specific LKB1 knock-out (KO) mice using alpha-myosin heavy chain-Cre deletor strain. LKB1-KO mice displayed biatrial enlargement with atrial fibrillation and cardiac dysfunction at 4 weeks of age. Left ventricular hypertrophy was observed in LKB1-KO mice at 12 weeks but not 4 weeks of age. Collagen I and III mRNA expression was elevated in atria at 4 weeks, and atrial fibrosis was seen at 12 weeks. LKB1-KO mice displayed cardiac dysfunction and atrial fibrillation and died within 6 months of age. Indicative of a prohypertrophic environment, the phosphorylation of AMPK and eEF2 was reduced, whereas mammalian target of rapamycin (mTOR) phosphorylation and p70S6 kinase phosphorylation were increased in both the atria and ventricles of LKB1-deficient mice. Consistent with vascular endothelial growth factor mRNA and protein levels being significantly reduced in LKB1-KO mice, these mice also exhibited a reduction in capillary density of both atria and ventricles. In cultured cardiac myocytes, LKB1 silencing induced hypertrophy, which was ameliorated by the expression of a constitutively active form AMPK or by treatment with the inhibitor of mTOR, rapamycin. These findings indicate that LKB1 signaling in cardiac myocytes is essential for normal development of the atria and ventricles. Cardiac hypertrophy and dysfunction in LKB1-deficient hearts are associated with alterations in AMPK and mTOR/p70S6 kinase/eEF2 signaling and with a reduction in vascular endothelial growth factor expression and vessel rarefaction.