期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1842, 期 9, 页码 1638-1647出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2014.06.002
关键词
Ischemic stress; Protein translation; RNA binding; Cardiac protection
资金
- NHLBI NIH HHS [R01 HL076530, R01 HL089958] Funding Source: Medline
- NIEHS NIH HHS [T32 ES007091, P30 ES006694, R21 ES017473] Funding Source: Medline
- NIGMS NIH HHS [R01 GM111337] Funding Source: Medline
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 Nr12 5' UTR. Ribonudeoprotein complex immunoprecipitation assays confirmed such association indeed occurring in vivo. Knocking down La using siRNA was able to prevent Nr12 protein elevation by oxidants in cultured cardiomyocytes and by cycles of 5'l/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 Nr12 mRNA in cardiomyocytes. (C) 2014 Elsevier B.V. All rights reserved.
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