A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the Nuclear Distribution of NT-PGC-1α in NRVMs

Zuheng Liu,Haiping Tian,Qingchun Zeng,Yujia Bai,Hao Ren,Wenyan Lai,Jinghai Hua,Dingli Xu,Qiong Zhan,Wanqiang Cai

doi:10.3389/fphar.2019.00465

Abstract

Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1α (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-1α is an alternative splicing variant of PGC-1α that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1α into the nucleus and activate PGC-1α target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1α and NT-PGC-1α 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 β-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1α or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1α and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1α. After NT-PGC-1α was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-α, Tfam, ERR-γ, 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-1α transportation.

Highlights

Rates of heart failure (HF) are rising at an alarming rate throughout the world (MartinezGonzalez and Ruiz-Canela, 2015)
We discovered that the neonatal rat ventricular myocytes (NRVMs) that were transfected with AdV-Nuclear localization sequence (NLS)-NT-PGC-1α and exposed to Selinexor could increase their relative amount of mRNA expression compared to cells that were transfected with AdVNLS-NT-PGC-1α (Figures 4C,D)
We suggest that the antihypertrophic effects of the Chromosomal maintenance 1 (CRM1) inhibitor Selinexor might be independent of NT-PGC-1α

Summary

Introduction

Rates of heart failure (HF) are rising at an alarming rate throughout the world (MartinezGonzalez and Ruiz-Canela, 2015). HF is commonly accompanied by cardiac hypertrophy (Warren et al, 2017). Additional studies on NT-PGC-1α, which is an alternative splicing variant of PGC-1α, have revealed that CRM1 inhibitors can lead to a relative. CRM1, NT-PGC-1α and Cardiac Hypertrophy increase in the nuclear distribution of NT-PGC-1α (Chang et al, 2010). The regulation of NT-PGC-1α by CRM1 inhibitors might represent a novel mechanism of their anticardiac-hypertrophy effect. A large amount of experimental evidence has demonstrated that HF is associated with metabolic dysfunction, which is accompanied by the down regulation of PGC-1α, a key factor in controlling mitochondrial energy metabolism (Arany et al, 2006; Schilling and Kelly, 2011; Arumugam et al, 2016). NT-PGC-1α is predominantly distributed in the cytoplasm, and the PGC1 families fulfill most of their function through the coactivation of transcription factors in the nucleus (Zhang et al, 2009)

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