Abstract 15571: Suppressing Increased Expression of NADPH-Dependent Malic Enzyme 1 in Hypertrophied Hearts Eliminates Maladaptive Anaplerosis and Improves Redox Conditions
The remodeled metabolic phenotype of hypertrophic hearts includes inefficient glucose oxidation, due in part to pyruvate carboxylation into anaplerosis. Increased carboxylation of pyruvate to malate via elevated malic enzme-1 (ME1) also consumes NADPH, which is necessary for maintaining glutathione reduction. Therefore, we studied the consequences of selective inhibition of ME1 expression via non-native miRNA targeted to the ME1 gene (miRME1) in hypertrophied rat hearts after transverse aortic constriction (TAC). TAC elevated ME1 content, but ME1 was lowered in hearts receiving miRME1 vs PBS infusion (*P<0.01). The effects of ME1 suppression on anaplerosis and GSH content were studied in isolated hearts supplied 13C palmitate, glucose, and lactate. While Sham miRME1 hearts showed no further reduction of inherently low baseline ratios of anaplerosis to citrate synthase flux from normal hearts, miRME1 reduced anaplerosis in TAC to baseline: TAC miRME1=0.034±0.004; TAC PBS=0.081±0.005 (*P<0.01, **P<0.001). Importantly, ME1 suppression restored GSH in TAC (†P<0.05). The findings demonstrate the maladaptive increase in anaplerosis via ME1 in TAC is associated with reduced GSH content. Suppressing increased ME1 expression in hypertrophied hearts, and thus consumption of NADPH for anaplerotic malate, produced favorable metabolic shifts, improving intracellular redox state.
Author Disclosures: R. Lahey: None. S.K. Fischer: None. X. Wang: None. J. Bi: None. A.N. Carley: None. J. O’Donnell: None. E. Lewandowski: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.