Lats2 is a negative regulator of myocyte size in the heart.
Lats2 is a negative regulator of myocyte size in the heart.
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DOI：
10.1161/circresaha.108.180042
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发表时间：
2008-11-21
影响因子：
20.1
通讯作者：
Sadoshima J
中科院分区：
文献类型：
--
作者：
Matsui Y;Nakano N;Shao D;Gao S;Luo W;Hong C;Zhai P;Holle E;Yu X;Yabuta N;Tao W;Wagner T;Nojima H;Sadoshima J
哺乳动物不育20样激酶1（Mst 1）在介导心脏细胞凋亡和抑制心脏肥大方面发挥重要作用。由于Hippo是Mst 1的果蝇同源物，与Warts（一种丝氨酸/苏氨酸激酶）形成信号复合物，进而刺激细胞死亡并抑制细胞增殖，因此Warts的哺乳动物同源物（称为Lats 1和Lats 2）可能介导Mst 1的功能。我们在这里表明，Lats 2，而不是Lats 1，在培养的心肌细胞凋亡的剂量依赖性增加。Lats 2还剂量依赖性地减少[3 H]苯丙氨酸掺入和心肌细胞大小，而显性负Lats 2（DN-Lats 2）增加它们，表明内源性Lats 2负调控心肌细胞生长。DN-Lats 2显著减弱了Mst 1诱导的细胞凋亡和抑制肥大，表明Lats 2介导了Mst 1在心肌细胞中的功能。在转基因小鼠中心脏特异性过表达Lats 2显著减小了左心室和右心室的大小，而DN-Lats 2的过表达导致了两个心室的肥大。过表达Lats 2降低左心室收缩和舒张功能，而不影响心肌细胞凋亡的基线水平。内源性Lats 2的表达显著上调响应于横向主动脉缩窄（TAC）。过表达DN-Lats 2可显著增强TAC诱导的心肌肥厚和抑制心肌细胞凋亡。这些结果表明，Lats 2是必要的和足够的负调节心室质量的心脏。虽然Lats 2是心肌细胞凋亡对压力超负荷的反应所必需的，但它不足以在基线诱导凋亡。总之，Lats 2影响心肌细胞的生长和死亡，但它主要调节心脏的大小，并作为心脏肥大的内源性负调节因子。
Mammalian sterile 20-like kinase 1 (Mst1) plays an important role in mediating apoptosis and inhibiting hypertrophy in the heart. Since Hippo, a Drosophila homologue of Mst1, forms a signaling complex with Warts, a serine/threonine kinase, which in turn stimulates cell death and inhibits cell proliferation, mammalian homologs of Warts, termed Lats1 and Lats2, may mediate the function of Mst1. We here show that Lats2, but not Lats1, dose dependently increased apoptosis in cultured cardiac myocytes. Lats2 also dose-dependently reduced [3H]phenylalanine incorporation and cardiac myocyte size, whereas dominant negative Lats2 (DN-Lats2) increased them, suggesting that endogenous Lats2 negatively regulates myocyte growth. DN-Lats2 significantly attenuated induction of apoptosis and inhibition of hypertrophy by Mst1, indicating that Lats2 mediates the function of Mst1 in cardiac myocytes. Cardiac specific overexpression of Lats2 in transgenic mice significantly reduced the size of left and right ventricles, whereas that of DN-Lats2 caused hypertrophy in both ventricles. Overexpression of Lats2 reduced left ventricular systolic and diastolic function without affecting baseline levels of myocardial apoptosis. Expression of endogenous Lats2 was significantly upregulated in response to transverse aortic constriction (TAC). Overexpression of DN-Lats2 significantly enhanced cardiac hypertrophy and inhibited cardiac myocyte apoptosis induced by TAC. These results suggest that Lats2 is necessary and sufficient for negatively regulating ventricular mass in the heart. Although Lats2 is required for cardiac myocyte apoptosis in response to pressure overload, it was not sufficient to induce apoptosis at baseline. In conclusion, Lats2 affects both growth and death of cardiac myocytes, but it primarily regulates the size of the heart and acts as an endogenous negative regulator of cardiac hypertrophy.