A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the Nuclear Distribution of NT-PGC-1α in NRVMs
A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the Nuclear Distribution of NT-PGC-1α in NRVMs
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CRM1 抑制剂可减轻心脏肥大并增加 NRVM 中 NT-PGC-1 α 的核分布
DOI：
10.3389/fphar.2019.00465
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发表时间：
2019-05-07
影响因子：
5.6
通讯作者：
Xu, Dingli
中科院分区：
文献类型：
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作者：
Liu, Zuheng;Tian, Haiping;Xu, Dingli
染色体维持1（CRM 1）抑制剂显示抗肥大作用，并控制蛋白质在细胞核和细胞质之间的运输。PGC-1 α（过氧化物酶体增殖物激活受体γ共激活因子-1 α）是一种主要存在于细胞核中的转录共激活因子，在心力衰竭期间下调。NT-PGC-1 α是PGC-1 α的选择性剪接变体，主要分布在细胞质中。我们假设使用CRM 1抑制剂可以将NT-PGC-1 α穿梭到细胞核中并激活PGC-1 α靶基因，从而可能改善心肌梗死（MI）小鼠模型的心脏功能。我们发现MI诱导的心力衰竭小鼠中PGC-1 α和NT-PGC-1 α降低。应用苯丙氨酸和血管紧张素II诱导新生大鼠心室肌细胞（NRVMs）肥大。CRM 1抑制剂Selinexor的抗肥大作用通过分析β-MHC的表达和通过可视化细胞横截面积来验证。用腺病毒-NT-PGC-1 α或腺病毒-NLS（核定位序列）-NT-PGC-1 α转染NRVM，然后暴露于Selinexor。然后使用共聚焦显微镜观察NT-PGC-1 α的穿梭。NT-PGC-1 α穿梭进入细胞核后，其相关基因的表达增加，包括PPAR-alpha，Tfam，ERR-γ，CPT 1b，PDK 4和Nrf 2。通过超声心动图和qPCR测定Selinexor对MI后C57 BL/6 j小鼠的作用。我们发现Selinexor显示抗肥大作用，但不影响MI小鼠的射血分数。有趣的是，Selinexor的抗肥大作用可能不依赖于NT-PGC-1 α转运。
Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is a type of transcriptional coactivator that predominantly resides in the nucleus and is downregulated during heart failure. NT-PGC-1 alpha is an alternative splicing variant of PGC-1 alpha that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1 alpha into the nucleus and activate PGC-1 alpha target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1 alpha and NT-PGC-1 alpha were decreased in MI-induced heart failure mice. Phenylephrine and angiotensin II were applied to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). The antihypertrophic effects of the CRM1-inhibitor Selinexor was verified through profiling the expression of beta-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1 alpha or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1 alpha and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1 alpha. After NT-PGC-1 alpha was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-alpha, Tfam, ERR-gamma, CPT1b, PDK4, and Nrf2. The effects of Selinexor on post-MI C57BL/6j mice were determined by echocardiography and qPCR. We found that Selinexor showed antihypertrophic effects but did not influence the ejection fraction of MI-mice. Interestingly, the antihypertrophic effects of Selinexor might be independent of NT-PGC-1 alpha transportation.