Allosteric activation of PP2A inhibits experimental abdominal aortic aneurysm.
Allosteric activation of PP2A inhibits experimental abdominal aortic aneurysm.
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DOI：
10.1042/cs20210315
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发表时间：
2021-09-17
期刊：
影响因子：
--
通讯作者：
Lin Z
中科院分区：
文献类型：
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作者：
Zhou X;Zhang C;Xie F;Wei W;Li R;Xu Q;Wang Y;Klenotic PA;Narla G;Dong N;Lin Z
尽管非常重要，但主动脉瘤(AA)形成和发展的分子机制仍然知之甚少。这一缺陷是开发治疗再生障碍性贫血的有效药物疗法的关键障碍。虽然蛋白磷酸酶2A(PP2A)的调节失调被认为在心血管疾病中发挥作用，但它在主动脉瘤中的作用尚不清楚。本研究的目的是在小鼠模型上验证PP2A调节腹主动脉瘤(AAA)进展的假设。在血管紧张素II诱导的AAA小鼠模型中，PP2A抑制剂LB-100显著加速了AAA的进展，表现为腹主动脉扩张和死亡率增加。AAA进展与炎症加重和细胞外基质碎裂有关，伴随着金属蛋白酶活性和活性氧产生的增加。相反，给予一类新的PP2A小分子激活剂(SMAP)会产生相反的效果。SMAP有效地降低了AAA的发生率，同时也增加了与LB-100处理相关的病理改变。在机制上，体内PP2A活性的调节部分是通过改变ERK1/2和NFκB信号通路来实现的，这两个信号通路是已知的AA进展的调节因素。这些研究首次证明了PP2A在AAA病因学中的作用，并证明PP2A激活可能是腹主动脉瘤治疗的一种新策略。
Although extremely important, the molecular mechanisms that govern aortic aneurysm (AA) formation and progression are still poorly understood. This deficit represents a critical road-block toward the development of effective pharmaceutical therapies for the treatment of AA. While dysregulation of protein phosphatase 2A (PP2A) is thought to play a role in cardiovascular disease, its role in aortic aneurysm is unknown. The objective of the present study is to test the hypothesis that PP2A regulates abdominal aortic aneurysm (AAA) progression in a murine model. In an angiotensin II-induced AAA murine model, the PP2A inhibitor, LB-100, markedly accelerated AAA progression as demonstrated by increased abdominal aortic dilation and mortality. AAA progression was associated with elevated inflammation and extracellular matrix fragmentation, concomitant with increases in both metalloproteinase activity and reactive oxygen species production. Conversely, administration of a novel class of small molecule activators of PP2A (SMAPs) resulted in an antithetical effect. SMAPs effectively reduced AAA incidence along with the corresponding pathologies that were increased with LB-100 treatment. Mechanistically, modulation of PP2A activities in vivo functioned in part via alteration of the ERK1/2 and NFκB signaling pathways, known regulators of AAA progression. These studies, for the first time, demonstrate a role of PP2A in AAA etiology and demonstrate that PP2A activation may represent a novel strategy for the treatment of abdominal aortic aneurysms.