Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension
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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 14C-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.
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.
KeywordsWarburg effect cMyc 6-Diazo-5-oxo-l-norleucine (DON) Glucose oxidation WHO group 1 pulmonary hypertension (PAH) Anapleurosis Congenital heart disease Scleroderma
Dr. Archer is supported by NIH-RO1-HL071115 and 1RC1HL099462-01 and the American Heart Association. The authors thank Dr. E. Kenneth Weir for his help in critiquing this manuscript.
The authors have no conflicts to disclose.
- 4.Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51PubMedCrossRefGoogle Scholar
- 6.Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J et al (2012) Lung (1)(8)F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185:670–679PubMedCrossRefGoogle Scholar
- 7.Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88:47–60PubMedCrossRefGoogle Scholar
- 9.Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, Thenappan T, Piao L, Zhang HJ, Pogoriler J et al (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110:1484–1497PubMedCrossRefGoogle Scholar
- 11.DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:19345–19350PubMedCrossRefGoogle Scholar
- 15.Bodi V, Sanchis J, Morales JM, Marrachelli VG, Nunez J, Forteza MJ, Chaustre F, Gomez C, Mainar L, Minana G et al (2012) Metabolomic profile of human myocardial ischemia by nuclear magnetic resonance spectroscopy of peripheral blood serum: a translational study based on transient coronary occlusion models. J Am Coll Cardiol 59:1629–1641PubMedCrossRefGoogle Scholar
- 17.Piao L, Fang YH, Parikh KS, Ryan JJ, D'Souza KM, Theccanat T, Toth PT, Pogoriler J, Paul J, Blaxall BC et al (2012) GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation 126:2859–2869PubMedCrossRefGoogle Scholar
- 28.Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB et al (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 105:18782–18787PubMedCrossRefGoogle Scholar