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

Zuheng Liu1,2, Haiping Tian1,2,3, Jinghai Hua1,2

  • 1State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Frontiers in Pharmacology
|May 29, 2019
PubMed

Insights

Chromosomal maintenance 1 (CRM1) inhibitors like Selinexor reduced heart cell size but did not improve heart function in mice after myocardial infarction. The antihypertrophic effects may not depend on shuttling NT-PGC-1α into the nucleus.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Signaling

Background:

  • Chromosomal maintenance 1 (CRM1) inhibitors impact protein trafficking and have shown antihypertrophic effects.
  • Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) is crucial for cardiac function and downregulated in heart failure.
  • NT-PGC-1α, a cytoplasmic variant, was investigated for nuclear translocation and potential therapeutic roles.

Purpose of the Study:

  • To investigate if CRM1 inhibition could shuttle NT-PGC-1α into the nucleus and activate target genes, potentially improving cardiac function post-myocardial infarction (MI).
  • To evaluate the antihypertrophic effects of the CRM1 inhibitor Selinexor in cellular and animal models of heart failure.

Main Methods:

  • Induced cardiac hypertrophy in neonatal rat ventricular myocytes (NRVMs) using phenylephrine and angiotensin II.
  • Treated NRVMs with Selinexor and assessed antihypertrophic effects via β-MHC expression and cell size.
  • Utilized confocal microscopy to observe NT-PGC-1α shuttling in transfected NRVMs.
  • Administered Selinexor to C57BL/6j mice post-MI and evaluated cardiac function using echocardiography and gene expression via qPCR.

Main Results:

  • PGC-1α and NT-PGC-1α levels were decreased in mice with MI-induced heart failure.
  • Selinexor demonstrated antihypertrophic effects in NRVMs, reducing cell size and β-MHC expression.
  • Nuclear translocation of NT-PGC-1α led to increased expression of target genes (PPAR-α, Tfam, ERR-γ, CPT1b, PDK4, Nrf2).
  • In post-MI mice, Selinexor reduced hypertrophy but did not improve ejection fraction.

Conclusions:

  • Selinexor exhibits antihypertrophic properties in cardiac cells and models of heart failure.
  • The observed antihypertrophic effects of Selinexor in post-MI mice may occur independently of NT-PGC-1α nuclear transport.
  • Further research is needed to elucidate the precise mechanisms underlying Selinexor's effects on cardiac hypertrophy.
Keywords:
CRM1NT-PGC-1αantihypertrophycardiac functionmyocardial infarctionnuclear distribution

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