Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling.
Heart failure (HF) is the leading cause of morbidity and mortality in the industrialized world. While the transcriptomic changes in end-stage failing myocardium have received much attention, no information is available on the gene expression patterns associated with the development of HF in large mammals. Therefore, we used a well-controlled canine model of tachycardia-induced HF to examine global gene expression in left ventricular myocardium with Affymetrix canine oligonucleotide arrays at various stages after initiation of rapid ventricular pacing (days 3, 7, 14, and 21). The gene expression data were complemented with measurements of action potential duration, conduction velocity, and left ventricular end diastolic pressure, and dP/dt(max) over the time course of rapid ventricular pacing. As a result, we present a phenotype-centered gene association network, defining molecular systems that correspond temporally to hemodynamic and electrical remodeling processes. Gene Ontology analysis revealed an orchestrated regulation of oxidative phosphorylation, ATP synthesis, cell signaling pathways, and extracellular matrix components, which occurred as early as 3 days after the initiation of ventricular pacing, coinciding with the early decline in left ventricular pump function and prolongation of action potential duration. The development of clinically overt left ventricular dysfunction was associated with few additional changes in the myocardial transcriptome. We conclude that the majority of tachypacing-induced transcriptional changes occur early after initiation of rapid ventricular pacing. As the transition to overt HF is characterized by few additional transcriptional changes, posttranscriptional modifications may be more critical in regulating myocardial structure and function during later stages of HF.
Gao
Zhong
Z
The Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Barth
Andreas S
AS
DiSilvestre
Deborah
D
Akar
Fadi G
FG
Tian
Yanli
Y
Tanskanen
Antti
A
Kass
David A
DA
Winslow
Raimond L
RL
Tomaselli
Gordon F
GF
D000200:Action Potentials; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000150:complications; D020257:Ventricular Remodeling / Q000502:physiology*
Circ Res. 1999 Mar 19;84(5):562-70
10082478
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W472-6
16845052
Bioinformatics. 2002 Jan;18(1):207-8
11836235
Circ Res. 1962 Mar;10:306-12
13922328
J Pharmacol Exp Ther. 2007 Apr;321(1):165-71
17215446
Mol Cell Biochem. 2005 Jan;268(1-2):103-10
15724443
J Am Coll Cardiol. 1997 Aug;30(2):576-84
9247535
Bioinformatics. 2004 Jun 12;20(9):1453-4
14871861
J Mol Cell Cardiol. 2006 Jan;40(1):76-86
16236311
Mol Cell Biochem. 1997 Dec;177(1-2):61-7
9450646
Circulation. 1992 Apr;85(4):1464-72
1555287
Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H1223-30
17434978
Genomics. 2004 Feb;83(2):281-97
14706457
Circ Res. 2004 Oct 1;95(7):717-25
15345654
Circ Res. 1999 Mar 19;84(5):571-86
10082479
Circ Res. 1996 Feb;78(2):262-73
8575070
Cardiovasc Res. 2001 Oct;52(1):103-10
11557238
Nat Genet. 2000 May;25(1):25-9
10802651
J Am Coll Cardiol. 2006 Oct 17;48(8):1610-7
17045896
Circulation. 1999 Nov 16;100(20):2113-8
10562269
Cardiovasc Res. 1999 May;42(2):270-83
10533566
Electrophoresis. 1998 Aug;19(11):2021-30
9740064
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
J Biol Chem. 1992 Mar 15;267(8):5317-23
1312087
Rev Cardiovasc Med. 2003;4 Suppl 2:S14-20
12776009
Physiol Genomics. 2003 Jan 15;12(2):97-112
12429867
Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1003-12
15105169
Circulation. 2002 Jul 23;106(4):423-9
12135940
Physiol Genomics. 2007 Mar 14;29(1):76-83
17164392
Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3524-31
17906102
J Hypertens. 2006 Jun;24(6):1097-104
16685210
J Cardiovasc Pharmacol. 2007 Jun;49(6):408-15
17577106