title: Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.
abstract: The rapid growth of cancer cells is permitted by metabolic changes, notably increased aerobic glycolysis and increased glutaminolysis. Aerobic glycolysis is also evident in the hypertrophying myocytes in right ventricular hypertrophy (RVH), particularly in association with pulmonary arterial hypertension (PAH). It is unknown whether glutaminolysis occurs in the heart. We hypothesized that glutaminolysis occurs in RVH and assessed the precipitating factors, transcriptional mechanisms, and physiological consequences of this metabolic pathway. RVH was induced in two models, one with PAH (Monocrotaline-RVH) and the other without PAH (pulmonary artery banding, PAB-RVH). Despite similar RVH, ischemia as determined by reductions in RV VEGFα, coronary blood flow, and microvascular density was greater in Monocrotaline-RVH versus PAB-RVH. A sixfold increase in (14)C-glutamine metabolism occurred in Monocrotaline-RVH but not in PAB-RVH. In the RV working heart model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) decreased glutaminolysis, caused a reciprocal increase in glucose oxidation, and elevated cardiac output. Consistent with the increased glutaminolysis in RVH, RV expressions of glutamine transporters (SLC1A5 and SLC7A5) and mitochondrial malic enzyme were elevated (Monocrotaline-RVH > PAB-RVH > control). Capillary rarefaction and glutamine transporter upregulation also occurred in RVH in patients with PAH. cMyc and Max, known to mediate transcriptional upregulation of glutaminolysis, were increased in Monocrotaline-RVH. In vivo, DON (0.5 mg/kg/day × 3 weeks) restored pyruvate dehydrogenase activity, reduced RVH, and increased cardiac output (89 ± 8, vs. 55 ± 13 ml/min, p < 0.05) and treadmill distance (194 ± 71, vs. 36 ±7 m, p < 0.05) in Monocrotaline-RVH. Glutaminolysis is induced in the RV in PAH by cMyc-Max, likely as a consequence of RV ischemia. Inhibition of glutaminolysis restores glucose oxidation and has a therapeutic benefit in vivo.
  
  
  CONCLUSIONS
  Patients with pulmonary artery hypertension (PAH) have evidence of cardiac glutaminolysis. Cardiac glutaminolysis is associated with microvascular rarefaction/ischemia. As in cancer, cardiac glutaminolysis results from activation of cMyc-Max. The specific glutaminolysis inhibitor DON regresses right ventricular hypertrophy. DON improves cardiac function and exercise capacity in an animal model of PAH.
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Piao
authors.forename: Yong-Hu
authors.initials: YH
authors.lastname: Fang
authors.forename: Kishan
authors.initials: K
authors.lastname: Parikh
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Peter T
authors.initials: PT
authors.lastname: Toth
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003980:Diazooxonorleucine / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000209:etiology; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D008297:Male; D008954:Models, Biological; D010084:Oxidation-Reduction; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; C037853:glutamine transport proteins; D003980:Diazooxonorleucine; D005973:Glutamine; D005947:Glucose