Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure.
Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of beta-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or beta-adrenergic receptor antagonists, demonstrating a proximal relationship among beta-adrenergic receptor function, Ca2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx and acute beta-adrenergic receptor stimulation. This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca2+ handling and beta-adrenergic receptor signaling.
Nakayama
Hiroyuki
H
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
Chen
Xiongwen
X
Baines
Christopher P
CP
Klevitsky
Raisa
R
Zhang
Xiaoying
X
Zhang
Hongyu
H
Jaleel
Naser
N
Chua
Balvin H L
BH
Hewett
Timothy E
TE
Robbins
Jeffrey
J
Houser
Steven R
SR
Molkentin
Jeffery D
JD
D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
D058672:Adrenergic beta-2 Receptor Antagonists; D020746:Calcium Channels, L-Type; D056741:Cyclin D; D016213:Cyclins; D018343:Receptors, Adrenergic, beta-2; D002118:Calcium
Circulation. 2000 Feb 8;101(5):558-69
10662755
Circulation. 2000 Apr 11;101(14):1707-14
10758054
J Biol Chem. 2000 May 5;275(18):13571-9
10788473
Cell. 2000 May 12;101(4):365-76
10830164
Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H429-36
10899083
J Card Fail. 2000 Jun;6(2 Suppl 1):1-7
10908092
Circ Res. 2003 May 2;92(8):904-11
12676813
Circ Res. 2003 May 2;92(8):912-9
12676814
Circ Res. 2003 May 2;92(8):897-903
12676818
J Clin Invest. 2003 May;111(10):1497-504
12750399
Cell Calcium. 2003 Jul;34(1):19-26
12767889
J Biol Chem. 2003 Jun 13;278(24):21623-30
12606548
Am J Pathol. 2006 Jun;168(6):1975-85
16723712
FASEB J. 2006 Aug;20(10):1660-70
16873889
Mol Cell. 2006 Sep 1;23(5):641-50
16949361
J Clin Invest. 2006 Dec;116(12):3114-26
17099778
Circ Res. 2007 Mar 2;100(4):536-44
17272809
Heart. 1999 Dec;82 Suppl 4:IV11-3
10574905
J Mol Cell Cardiol. 2000 Sep;32(9):1595-607
10966823
J Gene Med. 2000 Sep-Oct;2(5):326-33
11045426
J Clin Invest. 2000 Dec;106(11):1351-9
11104788
Circulation. 2001 Jan 2;103(1):140-7
11136699
Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2313-20
11299236
Am J Med. 2001 May 7;110 Suppl 7A:6S-13S
11334770
Cell. 2003 Jun 27;113(7):829-40
12837242
Am J Med. 2001 May 7;110 Suppl 7A:81S-94S
11334782
J Mol Cell Cardiol. 2001 May;33(5):1031-40
11343424
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5809-14
11331748
Nat Rev Mol Cell Biol. 2001 Jan;2(1):67-71
11413468
Fundam Clin Pharmacol. 2001 Apr;15(2):95-109
11468019
Am Heart J. 2001 Sep;142(3):393-401
11526351
FASEB J. 2001 Dec;15(14):2718-20
11606476
Cardiovasc Drugs Ther. 2001 Sep;15(5):375-7
11855655
Front Biosci. 2002 Apr 1;7:d843-52
11897570
J Clin Invest. 2002 Apr;109(8):1013-20
11956238
Biochimie. 2002 Feb-Mar;84(2-3):143-52
12022945
Circ Res. 2002 Sep 20;91(6):517-24
12242270
N Engl J Med. 2002 Oct 31;347(18):1397-402
12409541
Circulation. 2002 Dec 10;106(24):3068-72
12473553
J Clin Invest. 2003 Mar;111(5):617-25
12618516
Eur J Heart Fail. 2003 Mar;5(2):131-6
12644002
Circ Res. 2003 Apr 4;92(6):609-16
12623879
Exp Physiol. 2003 May;88(3):447-58
12719770
Nat Rev Mol Cell Biol. 2003 Jul;4(7):566-77
12838339
Nat Med. 2003 Sep;9(9):1187-94
12937413
Nat Med. 2003 Oct;9(10):1300-5
14502278
Circ Res. 2004 Jan 9;94(1):91-9
14615291
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):769-74
14715896
Cell. 2004 Jan 23;116(2):205-19
14744432
Recent Prog Horm Res. 2004;59:141-68
14749501
Circulation. 2004 Mar 9;109(9):1154-60
14967726
Trends Cardiovasc Med. 2004 Feb;14(2):61-6
15030791
J Biomed Sci. 2004 Sep-Oct;11(5):542-65
15316129
Circ Res. 2004 Sep 17;95(6):604-11
15308581
Circ Res. 1989 Jul;65(1):205-14
2544319
J Biol Chem. 1995 Dec 15;270(50):30036-44
8530407
Am J Physiol. 1996 Sep;271(3 Pt 2):H1215-28
8853362
Cell. 1997 Feb 7;88(3):393-403
9039266
Circ Res. 1997 May;80(5):655-64
9130446
Circulation. 1998 Sep 8;98(10):969-76
9737516
Am Heart J. 1999 Feb;137(2):352-60
9924171
J Am Coll Cardiol. 1999 Mar;33(3):734-42
10080475
Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7059-64
10359838
Am J Ther. 2004 Nov-Dec;11(6):467-72
15543087
J Clin Invest. 2005 Mar;115(3):556-64
15765137
J Clin Invest. 2005 Mar;115(3):565-71
15765138
Nature. 2005 Mar 31;434(7033):652-8
15800626
Nature. 2005 Mar 31;434(7033):658-62
15800627
Nature. 2005 Aug 18;436(7053):1025-9
16025101
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12005-10
16103352
Circ Res. 2005 Nov 11;97(10):1009-17
16210547
J Clin Invest. 2005 Dec;115(12):3306-17
16322774
Circ Res. 2005 Dec 9;97(12):1314-22
16269653
Biochem Soc Trans. 2006 Apr;34(Pt 2):232-7
16545083
Circ Res. 2006 Mar 31;98(6):837-45
16514068
Am J Physiol Heart Circ Physiol. 2006 May;290(5):H2024-34
16399872