Journal
BIOCHEMICAL JOURNAL
Volume 435, Issue -, Pages 519-528Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20101390
Keywords
aldehyde dehydrogenase (ALDH); cardiac hypertrophy; extracellular flux; glycolysis; 4-hydroxynonenal (HNE); mitochondrion
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Funding
- NIH-NHLBI (National Institutes of Health National Heart, Lung and Blood Institute) [R01 HL083320, R01 HL094419]
- American Heart Association National Center [0535270N]
- NIH-NCRR (National Institutes of Health National Center for Research Resources) [P20 RR024489]
- Kentucky Science and Engineering Foundation [KSEF-1677-RDE-011]
- NIH-NCRR [P20 RR024489]
- University of Louisville [20020]
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During cardiac remodelling, the heart generates higher levels of reactive species; yet an intermediate 'compensatory' stage of hypertrophy is associated with a greater ability to withstand oxidative stress. The mechanisms underlying this protected myocardial phenotype are poorly understood. We examined how a cellular model of hypertrophy deals with electrophilic insults, such as would occur upon ischaemia or in the failing heart. For this, we measured energetics in control and PE (phenylephrine)treated NRCMs (neonatal rat cardiomyocytes) under basal conditions and when stressed with HNE (4-hydroxynonenal). PE treatment caused hypertrophy as indicated by augmented atrial natriuretic peptide and increased cellular protein content. Hypertrophied myocytes demonstrated a 2.5-fold increase in ATP-linked oxygen consumption and a robust augmentation of oligomycin-stimutated glycolytic flux and lactate production. Hypertrophied myocytes displayed a protected phenotype that was resistant to HNE-induced cell death and a unique bioenergetic response characterized by a delayed and abrogated rate of oxygen consumption and a 2-fold increase in glycolysis upon HNE exposure. This augmentation of glycolytic flux was not due to increased glucose uptake, suggesting that electrophile stress results in utilization of intracellular glycogen stores to support the increased energy demand. Hypertrophied myocytes also had an increased propensity to oxidize HNE to 4-hydroxynonenoic acid and sustained less protein damage due to acute HNE insults. Inhibition of aldehyde dehythogenase resulted in bioenergetic collapse when myocytes were challenged with HNE. The integration of electrophile metabolism with glycolytic and mitochondrial energy production appears to be important for maintaining myocyte homoeostasis under conditions of increased oxidative stress.
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