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

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.