Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart.
Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart.
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DOI：
10.1161/circulationaha.111.048785
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发表时间：
2011-12-13
期刊：
影响因子：
37.8
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Liu W;Zi M;Naumann R;Ulm S;Jin J;Taglieri DM;Prehar S;Gui J;Tsui H;Xiao RP;Neyses L;Solaro RJ;Ke Y;Cartwright EJ;Lei M;Wang X
应激性肥厚性重构是导致心力衰竭的重要病理过程。虽然许多信号传导级联被证明是促进心脏肥大诱导的重要调节因子，但抑制肥大性重塑的信号通路在很大程度上仍未被探索。在这项研究中，我们确定p21激活激酶1（Pak1）作为一种新的信号调节剂，拮抗心肌肥厚。应用于原代新生大鼠心肌细胞（NRCM）或小鼠心脏的肥大应激引起Pak 1的激活。对表达组成型活性Pak 1或Pak 1沉默的NRCM的分析揭示，Pak 1发挥抗肥大作用。为了研究Pak1在心脏中的体内作用，我们产生了心肌细胞特异性缺失Pak1（Pak1cko）的小鼠。当经受2周的压力超负荷时，与对照组相比，Pak1cko小鼠出现了更大的心脏肥大，伴随着JNK激活的钝化，并且当施加长时间的压力时，这些敲除小鼠经历了向心力衰竭的转变。此外，慢性血管紧张素II输注也导致Pak1cko小鼠心脏肥大增加。此外，我们发现Pak 1激活剂FTY 720（一种鞘氨醇类似物）能够预防野生型小鼠的压力超负荷诱导的肥大，而不会损害其心脏功能。而FTY 720对Pak1cko小鼠则无此作用，提示FTY 720的抗肥大作用可能是通过激活Pak1而起作用的。这些结果，第一次，建立Pak1作为一种新的抗肥大调节剂，并表明它可能是一个潜在的治疗靶点，用于治疗心脏肥大和心力衰竭。
Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. While many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator which antagonizes cardiac hypertrophy. Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs), or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an anti-hypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1cko). When subject to 2 weeks of pressure overload, Pak1cko mice compared to controls, developed greater cardiac hypertrophy with attendant blunting of JNK activation, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. In addition, chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1cko mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analogue, was able to prevent pressure overload-induced hypertrophy in wild-type mice, without compromising their cardiac functions. Meanwhile FTY720 failed to exert such an effect on Pak1cko mice, suggesting that the anti-hypertrophic effect of FTY720 likely acts through Pak1 activation. These results, for the first time, establish Pak1 as a novel anti-hypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.