Myocardial ischemic reperfusion induces de novo Nrf2 protein translation

Beibei Xu, Jack Zhang, Joshua Strom, Sang Lee, Qin Chen

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Nrf2 is a bZIP transcription factor regulating the expression of antioxidant and detoxification genes. We have found that Nrf2 knockout mice have an increased infarction size in response to regional ischemic reperfusion and have a reduced degree of cardiac protection by means of ischemic preconditioning. With cycles of brief ischemia and reperfusion (5'I/5'R) that induce cardiac protection in wild type mice, an elevated Nrf2 protein was observed without prior increases of Nrf2 mRNA. When an mRNA species is being translated into a protein, it is occupied by multiple ribosomes. The level of ribosome-associated Nrf2 mRNA increased following cycles of 5'I/5'R, supporting de novo Nrf2 protein translation. A dicistronic reporter assay indicated a role of the 5' untranslated region (5' UTR) of Nrf2 mRNA in oxidative stress induced Nrf2 protein translation in isolated cardiomyocytes. Western blot analyses after isolation of proteins binding to biotinylated Nrf2 5' UTR from the myocardium or cultured cardiomyocytes demonstrated that cycles of 5'I/5'R or oxidants caused an increased association of La protein with Nrf2 5' UTR. Ribonucleoprotein complex immunoprecipitation assays confirmed such association indeed occurring in vivo. Knocking down La using siRNA was able to prevent Nrf2 protein elevation by oxidants in cultured cardiomyocytes and by cycles of 5'I/5'R in the myocardium. Our data point out a novel mechanism of cardiac protection by de novo Nrf2 protein translation involving interaction of La protein with 5' UTR of Nrf2 mRNA in cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)1638-1647
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number9
DOIs
StatePublished - 2014

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Myocardial Reperfusion
Protein Biosynthesis
5' Untranslated Regions
Cardiac Myocytes
Messenger RNA
Ribosomes
Oxidants
Reperfusion
Myocardium
Proteins
Basic-Leucine Zipper Transcription Factors
Ischemic Preconditioning
Ribonucleoproteins
Immunoprecipitation
Protein Binding
Knockout Mice
Infarction
Small Interfering RNA
Oxidative Stress
Ischemia

Keywords

  • Cardiac protection
  • Ischemic stress
  • Protein translation
  • RNA binding

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Myocardial ischemic reperfusion induces de novo Nrf2 protein translation. / Xu, Beibei; Zhang, Jack; Strom, Joshua; Lee, Sang; Chen, Qin.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 9, 2014, p. 1638-1647.

Research output: Contribution to journalArticle

Xu, Beibei ; Zhang, Jack ; Strom, Joshua ; Lee, Sang ; Chen, Qin. / Myocardial ischemic reperfusion induces de novo Nrf2 protein translation. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2014 ; Vol. 1842, No. 9. pp. 1638-1647.
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