Enhanced Redox State and Efficiency of Glucose Oxidation with miR Based Suppression of Maladaptive NADPH-Dependent Malic Enzyme 1 Expression in Hypertrophied Hearts
Rationale: Metabolic remodeling in hypertrophic hearts includes inefficient glucose oxidation via increased anaplerosis fueled by pyruvate carboxylation. Pyruvate carboxylation to malate through elevated malic enzme-1 (ME1) consumes NADPH necessary for reduction of glutathione and maintenance of intracellular redox state.
Objective: To elucidate upregulated ME1 as a potential maladaptive mechanism for inefficient glucose oxidation and compromised redox state in hypertrophied hearts.
Methods and Results: ME1 expression was selectively inhibited, in vivo, via non-native miRNA specific to ME1 (miR-ME1) in pressure-overloaded rat hearts. Rats subjected to transverse aortic constriction (TAC) or Sham surgery received either miR-ME1 or PBS. Effects of ME1 suppression on anaplerosis and GSH content were studied in isolated hearts supplied 13C-enriched substrate: palmitate, glucose, and lactate. Human myocardium collected from failing and nonfailing hearts during surgery enabled rtPCR confirmation of elevated ME1 gene expression in clinical heart failure versus non-failing human hearts (P<0.04). TAC induced elevated ME1 content, but ME1 was lowered in hearts infused with miR-ME1 versus PBS. While Sham miRME1 hearts showed no further reduction of inherently low anaplerosis in normal heart, miRME1 reduced anaplerosis in TAC to baseline: TAC miRME1=0.034±0.004; TAC PBS=0.081±0.005 (P<0.01). Countering elevated anaplerosis in TAC shifted pyruvate toward oxidation in the tricarboxylic acid cycle. Importantly, via the link to NADPH consumption by pyruvate carboxylation, ME1 suppression in TAC restored GSH content, reduced lactate production, and ultimately improved contractility.
Conclusions: A maladaptive increase in anaplerosis via ME1 in TAC is associated with reduced GSH content. Suppressing increased ME1 expression in hypertrophied rat hearts, which is also elevated in failing human hearts, reduced pyruvate carboxylation thereby normalizing anaplerosis, restoring GSH content and reducing lactate accumulation. Reducing ME1 induced favorable metabolic shifts for carbohydrate oxidation, improving intracellular redox state and enhancing cardiac performance in pathological hypertrophy.
- Received January 3, 2018.
- Revision received January 25, 2018.
- Accepted January 29, 2018.