Unfolded protein response regulates cardiac sodium current in systolic human heart failure

Ge Gao, An Xie, Jianhua Zhang, Amanda M. Herman, Euy Myoung Jeong, Lianzhi Gu, Man Liu, Kai Chien Yang, Timothy J. Kamp, Samuel C. Dudley

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background: Human heart failure (HF) increases alternative mRNA splicing of the type V, voltage-gated cardiac Na+ channel α-subunit (SCN5A), generating variants encoding truncated, nonfunctional channels that are trapped in the endoplasmic reticulum. In this work, we tested whether truncated Na + channels activate the unfolded protein response (UPR), contributing to SCN5A electric remodeling in HF. Methods and Results: UPR and SCN5A were analyzed in human ventricular systolic HF tissue samples and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Cells were exposed to angiotensin II (AngII) and hypoxia, known activators of abnormal SCN5A mRNA splicing, or were induced to overexpress SCN5A variants. UPR effectors, protein kinase R-like ER kinase (PERK), calreticulin, and CHOP, were increased in human HF tissues. Induction of SCN5A variants with AngII or hypoxia or the expression of exogenous variants induced the UPR with concomitant downregulation of Na + current. PERK activation destabilized SCN5A and, surprisingly, Kv4.3 channel mRNAs but not transient receptor potential cation channel M7 (TRPM7) channel mRNA. PERK inhibition prevented the loss of fulllength SCN5A and Kv4.3 mRNA levels resulting from expressing Na+ channel mRNA splice variants. Conclusions: UPR can be initiated by Na+ channel mRNA splice variants and is involved in the reduction of cardiac Na+ current during human HF. Because the effect is not entirely specific to the SCN5A transcript, the UPR may play an important role in downregulation of multiple cardiac genes in HF.

Original languageEnglish (US)
Pages (from-to)1018-1024
Number of pages7
JournalCirculation: Arrhythmia and Electrophysiology
Volume6
Issue number5
DOIs
StatePublished - Oct 2013

Keywords

  • Heart failure
  • Humans
  • PERK kinase
  • Sodium channels

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