Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response

Peter J. Belmont, Wenqiong J. Chen, Donna J. Thuerauf, Christopher C. Glembotski

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

A nodal regulator of endoplasmic reticulum stress is the transcription factor, ATF6, which is activated by ischemia and protects the heart from ischemic damage, . in vivo. To explore mechanisms of ATF6-mediated protection in the heart, a whole-genome microRNA (miRNA) array analysis of RNA from the hearts of ATF6 transgenic (TG) mice was performed. The array identified 13 ATF6-regulated miRNAs, eight of which were downregulated, suggesting that they could contribute to increasing levels of their mRNAs. The down-regulated miRNAs, including miR-455, were predicted to target 45 mRNAs that we had previously shown by microarray analysis to be up-regulated by ATF6 in the heart. One of the miR-455 targets was calreticulin (. Calr), which is up-regulated in the pathologic heart, where it modulates hypertrophic growth, potentially reducing the impact of the pathology. To validate the effects of miR-455, we showed that Calr protein was increased by ATF6 in mouse hearts, . in vivo. In cultured cardiac myocytes, treatment with the ER stressor, tunicamycin, or with adenovirus encoding activated ATF6 decreased miR-455 and increased Calr levels, consistent with the effects of ATF6 on miR-455 and Calr, . in vivo. Moreover, transfection of cultured cardiac myocytes with a synthetic precursor, premiR-455, decreased Calr levels, while transfection with an antisense, antimiR-455, increased Calr levels. The results of this study suggest that ER stress can regulate gene expression . via ATF6-mediated changes in micro-RNA levels. Moreover, these findings support the hypothesis that ATF6-mediated down-regulation of miR-455 augments . Calr expression, which may contribute to the protective effects of ATF6 in the heart.

Original languageEnglish (US)
Pages (from-to)1176-1182
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume52
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Keywords

  • ATF6
  • Calreticulin
  • Cardiac
  • ER stress
  • MiRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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