Alterations of gene expression in failing myocardium following left ventricular assist device support.
Chronic unloading of the failing heart with a left ventricular assist device (LVAD) can decrease cardiac mass and myocyte size and has the potential to improve contractile function. To study the effect of chronic ventricular unloading on myocardial gene expression, a microarray (U133A, Affymetrix) profiling gene expression was compared before and after LVAD support in seven patients with idiopathic dilated cardiomyopathy and end-stage heart failure. On average, 1,374 +/- 155 genes were reported as "increased" and 1,629 +/- 45 as "decreased" after LVAD support. A total of 130 gene transcripts achieved the strict criteria for upregulation and 49 gene transcripts for downregulation after LVAD support. Upregulated genes included a large proportion of transcription factors, genes related to cell growth/apoptosis/DNA repair, cell structure proteins, metabolism, and cell signaling/communication. LVAD support resulted in downregulation of genes for a group of cytokines. To validate the array data, 10 altered genes were confirmed by real-time RT-PCR. Further study showed that the phosphoinositide-3-kinase-forkhead protein pathway and proteins related to nitric oxide synthesis, including eNOS and dimethylarginine dimethylaminohydrolase isoform 1 (DDAH1, an enzyme regulating endogenous nitric oxide synthase activity), were significantly increased during the cardiac remodeling process. Increased eNOS and DDAH1 expression after LVAD support may contribute to improved endothelial function of the failing hearts.
Chen
YingJie
Y
Department of Medicine (Cardiovascular Division), University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455, USA.
Park
Soon
S
Li
Yunfang
Y
Missov
Emil
E
Hou
Mingxiao
M
Han
Xinqiang
X
Hall
Jennifer L
JL
Miller
Leslie W
LW
Bache
Robert J
RJ
D000328:Adult; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020257:Ventricular Remodeling / Q000235:genetics
D009569:Nitric Oxide; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III