Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis
Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis
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DOI：
10.1038/nm.4364
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发表时间：
2017-08-01
期刊：
影响因子：
82.9
通讯作者：
Malumbres, Marcos
中科院分区：
文献类型：
--
作者：
de Carcer, Guillermo;Wachowicz, Paulina;Malumbres, Marcos
Polo样激酶1（PLK1）是细胞分裂的重要调节因子，目前正作为癌症治疗的靶点进行临床评估。我们报告了一个意想不到的功能Plk 1在维持心血管稳态。Plk1单倍不足小鼠没有引起明显的细胞增殖缺陷，但确实导致动脉结构改变，这经常导致主动脉破裂和死亡。特异性消融血管平滑肌细胞（VSMCs）中的Plk 1导致动脉弹性降低、低血压和体内对血管紧张素II的动脉反应受损。从机制上讲，我们发现Plk1调节血管紧张素II依赖性激活RhoA和肌动球蛋白动力学在VSMCs中的有丝分裂独立的方式。这种调节依赖于Plk1激酶的活性，并且向血管紧张素II治疗的小鼠施用小分子Plk1抑制剂导致动脉适应性降低以及动脉瘤和主动脉破裂的风险升高。因此，我们得出结论，Plk1活性的部分减少，不阻止细胞分裂，但可以损害主动脉的稳态。我们的研究结果对目前旨在抑制PLK1用于癌症治疗的方法具有潜在的重要意义。
Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.