Upregulation of autophagy genes and the unfolded protein response in human heart failure

Brian C. Jensen, Scott J. Bultman, Darcy Holley, Wei Tang, Gustaaf de Ridder, Salvatore Pizzo, Dawn Bowles, Monte Willis

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The cellular environment of the mammalian heart constantly is challenged with environmental and intrinsic pathological insults, which affect the proper folding of proteins in heart failure. The effects of damaged or misfolded proteins on the cell can be profound and result in a process termed “proteotoxicity”. While proteotoxicity is best known for its role in mediating the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, its role in human heart failure also has been recognized. The UPR involves three branches, including PERK, ATF6, and IRE1. In the presence of a misfolded protein, the GRP78 molecular chaperone that normally interacts with the receptors PERK, ATF6, and IRE-1 in the endoplasmic reticulum detaches to attempt to stabilize the protein. Mouse models of cardiac hypertrophy, ischemia, and heart failure demonstrate increases in activity of all three branches after removing GRP78 from these internal receptors. Recent studies have linked elevated PERK and CHOP in vitro with regulation of ion channels linked with human systolic heart failure. With this in mind, we specifically investigated ventricular myocardium from 10 patients with a history of conduction system defects or arrhythmias for expression of UPR and autophagy genes compared to myocardium from non-failing controls. We identified elevated Chop, Atf3, and Grp78 mRNA, along with XBP-1-regulated Cebpa mRNA, indicative of activation of the UPR in human heart failure with arrhythmias.

Original languageEnglish (US)
Article numberIJCEM0040108
Pages (from-to)1051-1058
Number of pages8
JournalInternational Journal of Clinical and Experimental Medicine
Volume10
Issue number1
StatePublished - Jan 30 2017
Externally publishedYes

Keywords

  • CHOP
  • GRP78
  • Heart failure
  • IRE-1
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Jensen, B. C., Bultman, S. J., Holley, D., Tang, W., de Ridder, G., Pizzo, S., Bowles, D., & Willis, M. (2017). Upregulation of autophagy genes and the unfolded protein response in human heart failure. International Journal of Clinical and Experimental Medicine, 10(1), 1051-1058. [IJCEM0040108].