Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading.
BACKGROUND
We have previously shown that several metabolic genes are downregulated in the failing human heart. We now tested the hypothesis that mechanical unloading might reverse this process.


METHODS
Clinical data and myocardial tissue were collected from 14 failing hearts paired for the time of implantation and explantation of a left ventricular assist device (LVAD) and compared to 10 non-failing hearts. Transcript levels for key regulators of energy metabolism and for atrial natriuretic factor (ANF) were measured by real-time quantitative RT-PCR.


RESULTS
The expression of the glucose transporter 1 and 4 (GLUT1, GLUT4), muscle carnitine palmitoyl transferase-1 (mCPT-1), and uncoupling protein 3 (UCP3) were downregulated by up to 80% in the failing heart. Although LVAD treatment improved clinical markers of heart failure (decrease of left ventricular diastolic dimension and normalization of serum sodium), only UCP3 expression reversed to non-failing transcript levels following mechanical unloading.


CONCLUSIONS
LVAD treatment only partially reverses depressed metabolic gene expression in the failing human heart. Reversal of depressed UCP3 expression may be an important mechanism for reducing the formation of oxygen-derived free radicals. Further studies are necessary to define the effects of mechanical unloading on post-transcriptional mechanisms.
Razeghi
Peter
P
Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030, USA.
Young
Martin E
ME
Ying
Jun
J
Depre
Christophe
C
Uray
Ivan P
IP
Kolesar
June
J
Shipley
Gregory L
GL
Moravec
Christine S
CS
Davies
Peter J A
PJ
Frazier
O H
OH
Taegtmeyer
Heinrich
H
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006333:Heart Failure / Q000235:genetics* / Q000601:surgery*; D006353:Heart-Assist Devices; D006801:Humans; D007473:Ion Channels; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013781:Texas; D016896:Treatment Outcome; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4