Myocardial function with reduced expression of the sodium-calcium exchanger.
BACKGROUND
The complete removal of the cardiac sodium-calcium exchanger (NCX1) is associated with embryonic lethality, whereas its overexpression is linked to heart failure. To determine whether or not a reduced expression of NCX1 is compatible with normal heart structure and function, we studied 2 knockout (KO) mouse models with reduced levels of NCX1: a heterozygous global KO (HG-KO) with a 50% level of NCX1 expression in all myocytes, and a ventricular-specific KO (V-KO) with NCX1 expression in only 10% to 20% of the myocytes.


RESULTS
Both groups of mice were evaluated at baseline, after transaortic constriction (TAC), and after acute or chronic beta-adrenergic stimulation. At baseline, the HG-KO mice had smaller hearts and the V-KO mice had larger hearts than their wild-type (WT) controls (P < .05). The HG-KO and their control WT mice had normal responses to TAC and beta-adrenergic stimulation. However, the V-KO group was intolerant to TAC and had a significantly (P < .05) blunted response to beta-adrenergic stimulation as compared with the HG-KO mice and WT controls. Unlike the HG-KO mice, the V-KO mice did not tolerate chronic isoproterenol infusion. Telemetric analysis of the electrocardiogram, body temperature, and activity revealed a normal diurnal rhythm in all groups of mice, but confirmed shorter QT intervals along with increased arrhythmias and reduced R wave to P wave amplitude ratios in the V-KO mice.


CONCLUSIONS
Though NCX1 can be reduced by half in all myocytes without significant functional alterations, it must be expressed in more than 20% of the myocytes to prevent severe remodeling and heart failure in mouse heart.
Jordan
Maria C
MC
Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. mjordan@mednet.ucla.edu
Henderson
Scott A
SA
Han
Tieyan
T
Fishbein
Michael C
MC
Philipson
Kenneth D
KD
Roos
Kenneth P
KP
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000473:pathology; D002302:Cardiac Output; D004195:Disease Models, Animal; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000473:pathology*; D006439:Hemodynamics; D007545:Isoproterenol / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis* / Q000187:drug effects; D014463:Ultrasonography
D000318:Adrenergic beta-Agonists; D019831:Sodium-Calcium Exchanger; D007545:Isoproterenol
Biochem Biophys Res Commun. 2004 Oct 1;322(4):1336-40
15336980
FASEB J. 2002 Mar;16(3):373-8
11874986
Cardiovasc Res. 1998 Feb;37(2):279-89
9614485
J Am Assoc Lab Anim Sci. 2006 Jul;45(4):8-13
16884172
Circ Res. 2008 May 9;102(9):1109-17
18340010
Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8277-81
1832775
Annu Rev Physiol. 2000;62:111-33
10845086
J Card Fail. 2007 May;13(4):318-29
17517353
Am J Physiol. 1993 Sep;265(3 Pt 2):H1024-9
8214109
Mol Genet Metab. 2005 Sep-Oct;86(1-2):233-43
15979918
Circ Res. 2005 Oct 28;97(9):916-21
16179590
Ann N Y Acad Sci. 2007 Mar;1099:270-5
17446467
Circ Res. 2004 Sep 17;95(6):604-11
15308581
Circ Res. 2002 Feb 22;90(3):305-8
11861419
Circ Res. 2003 Nov 14;93(10):896-906
14615493
Am J Physiol Cell Physiol. 2007 Feb;292(2):C968-73
16943244
N Engl J Med. 1982 Jul 22;307(4):205-11
6283349
FASEB J. 2001 May;15(7):1209-11
11344090
Circ Res. 1994 Sep;75(3):443-53
8062418
Cardiol Rev. 2009 Nov-Dec;17(6):300-3
19829181
Circulation. 1996 Sep 1;94(5):1109-17
8790053
Hum Mol Genet. 2005 Jul 15;14(14):1921-33
15917272
J Biol Chem. 2000 Nov 24;275(47):36991-8
10967099
Can J Physiol Pharmacol. 2004 Mar;82(3):167-74
15052282
Am J Physiol. 1992 Nov;263(5 Pt 2):H1506-13
1443202
J Pharmacol Sci. 2004 Sep;96(1):23-6
15359083
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17699-704
16314583
Life Sci. 2002 Aug 2;71(11):1279-92
12106593
J Mol Cell Cardiol. 2007 Apr;42(4):804-11
17350036
Circ Res. 2005 Dec 9;97(12):1288-95
16293789
J Mol Cell Cardiol. 2000 Sep;32(9):1595-607
10966823