SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.
Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.
Department of Pharmacology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0575, USA. wanghs@uc.edu
Hong-Sheng
HS
Wang
Demetrios A
DA
Arvanitis
Min
M
Dong
Paul J
PJ
Niklewski
Wen
W
Zhao
Chi Keung
CK
Lam
Evangelia G
EG
Kranias
Despina
D
Sanoudou
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D004594:Electrophysiology; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
Cell. 1999 Nov 24;99(5):485-97
10589677
Cardiovasc Res. 2002 Mar;53(4):782-805
11922890
Annu Rev Physiol. 1982;44:401-23
6280588
Basic Res Cardiol. 2002;97 Suppl 1:I36-42
12479232
Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1378-403
15142845
J Biol Chem. 2007 Sep 14;282(37):26897-26907
17631495
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93
16432188
J Neurophysiol. 2004 Apr;91(4):1556-69
14657190
J Mol Cell Cardiol. 2006 Nov;41(5):753-61
16962130
J Immunol. 2002 Nov 15;169(10):5941-7
12421979
Circ Res. 2007 Jan 5;100(1):112-20
17110593
Nat Biotechnol. 2006 Sep;24(9):1151-61
16964229
J Biol Chem. 1998 Feb 20;273(8):4734-9
9468536
J Biol Chem. 2004 May 21;279(21):22331-46
15024025
Circulation. 2006 Feb 21;113(7):995-1004
16476846
Cardiovasc Res. 1997 Jul;35(1):2-3
9302340
Science. 2003 Feb 28;299(5611):1410-3
12610310
Nature. 2000 Mar 16;404(6775):298-302
10749215
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4666-71
12677001
Exp Cell Res. 2002 Feb 1;273(1):34-44
11795944
J Cell Biol. 2007 Oct 8;179(1):129-38
17908914
J Physiol. 2005 May 1;564(Pt 3):683-96
15746173
J Biol Chem. 2000 Apr 7;275(14):10538-44
10744747
Circulation. 2007 Jan 23;115(3):300-9
17224479
Trends Cardiovasc Med. 2004 Feb;14(2):61-6
15030791
J Cardiovasc Pharmacol Ther. 2004 Jun;9(2):129-44
15309249
J Mol Cell Cardiol. 2001 May;33(5):851-72
11343410
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3289-93
8159741
Cell. 2003 May 16;113(4):483-94
12757709
Circ Res. 2008 May 23;102(10):1239-46
18403730
BMC Biotechnol. 2003 Jun 11;3:6
12801425
J Biol Chem. 2001 May 25;276(21):17706-11
11279089
J Biol Chem. 2003 Mar 14;278(11):9778-83
12511555
J Neurosci. 1998 Jan 1;18(1):128-37
9412493
Nat Rev Mol Cell Biol. 2003 Jul;4(7):566-77
12838339
Nature. 2007 Sep 20;449(7160):336-40
17882219
Nat Genet. 1998 Jan;18(1):15-7
9425891
Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H631-7
16565319
J Mol Endocrinol. 2004 Apr;32(2):481-96
15072553
Biotechniques. 1995 Jun;18(6):995-8
7546726
Cardiovasc Res. 2004 Aug 15;63(3):423-32
15276467
Physiol Genomics. 2005 Feb 10;20(3):256-67
15623567
Ann Med. 2000 Nov;32(8):572-8
11127935
J Biol Chem. 1986 Feb 5;261(4):1794-800
2935532
J Mol Cell Cardiol. 2001 Jul;33(7):1345-53
11437540
Cardiovasc Res. 2002 Nov;56(2):248-59
12393095