title: Unfolded protein response regulates cardiac sodium current in systolic human heart failure.
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.
  
  
  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 full-length 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.
authors.affiliation: Lifespan Cardiovascular Research Center, the Warren Alpert School of Medicine, Brown University and Providence Veterans Administration Medical Center, Providence, RI.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.forename: An
authors.initials: A
authors.lastname: Xie
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Herman
authors.forename: Euy-Myoung
authors.initials: EM
authors.lastname: Jeong
authors.forename: Lianzhi
authors.initials: L
authors.lastname: Gu
authors.forename: Man
authors.initials: M
authors.lastname: Liu
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D022062:Electrophysiologic Techniques, Cardiac; D004721:Endoplasmic Reticulum / Q000378:metabolism; D054143:Heart Failure, Systolic / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015222:Sodium Channels / Q000378:metabolism*; D014162:Transfection; D056811:Unfolded Protein Response / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D037282:Calreticulin; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568320:SCN5A protein, human; D015222:Sodium Channels; D000804:Angiotensin II; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: PERK kinase; heart failure; humans; sodium channels
references.citation: Cell Cycle. 2008 May 1;7(9):1146-50
references.pmid: 18418049
references.citation: Circulation. 2004 Aug 10;110(6):705-12
references.pmid: 15289376
references.citation: Am J Physiol Cell Physiol. 2009 Mar;296(3):C393-402
references.pmid: 19005161
references.citation: Circ Res. 2009 Feb 13;104(3):328-36
references.pmid: 19106412
references.citation: Biochem Biophys Res Commun. 2008 Nov 14;376(2):315-20
references.pmid: 18782560
references.citation: Circ Res. 2003 Sep 5;93(5):472-8
references.pmid: 12893738
references.citation: Circ Res. 2012 Oct 12;111(9):1125-36
references.pmid: 22912385
references.citation: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1411-20
references.pmid: 16617122
references.citation: Circ Res. 2007 Nov 26;101(11):1146-54
references.pmid: 17901361
references.citation: Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H945-55
references.pmid: 20044444
references.citation: J Mol Cell Cardiol. 2005 Mar;38(3):475-83
references.pmid: 15733907
references.citation: Science. 2009 May 8;324(5928):797-801
references.pmid: 19325077
references.citation: Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):554-8
references.pmid: 1309946
references.citation: Circ Res. 2012 Oct 12;111(9):1137-46
references.pmid: 22896586
references.citation: Circulation. 1997 Jul 15;96(2):526-34
references.pmid: 9244221
references.citation: Arch Toxicol. 2009 Feb;83(2):151-9
references.pmid: 18696052
references.citation: FEBS Lett. 2000 Aug 11;479(1-2):29-34
references.pmid: 10940383
references.citation: J Biol Chem. 2008 Feb 8;283(6):3097-3108
references.pmid: 18063576
references.citation: Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1636-45
references.pmid: 17545481
references.citation: Cardiovasc Res. 1999 Sep;43(4):838-49
references.pmid: 10615411
references.citation: Circulation. 1998 Oct 6;98(14):1383-93
references.pmid: 9760292
references.citation: Eur Heart J. 2011 Feb;32(3):305-15
references.pmid: 21148163
references.citation: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2077-87
references.pmid: 15637125
references.citation: J Am Coll Cardiol. 2005 Dec 6;46(11):2100-6
references.pmid: 16325048
references.citation: J Mol Cell Cardiol. 2008 Mar;44(3):453-9
references.pmid: 18054039
references.citation: Biochem Biophys Res Commun. 2006 Nov 3;349(4):1406-11
references.pmid: 16979584
references.citation: Am J Physiol Cell Physiol. 2007 Feb;292(2):C756-66
references.pmid: 16987996
references.citation: Curr Cardiol Rep. 2000 Nov;2(6):507-14
references.pmid: 11060577
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H416-24
references.pmid: 18515646
references.citation: Cardiovasc Res. 2009 Nov 1;84(2):227-36
references.pmid: 19567484
references.citation: J Clin Invest. 2005 Mar;115(3):500-8
references.pmid: 15765131
references.citation: Heart Rhythm. 2012 May;9(5):760-9
references.pmid: 22155597
references.citation: Circulation. 2011 Sep 6;124(10):1124-31
references.pmid: 21859973