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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 VEGF?, 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?

SUBMITTER: Piao L

PROVIDER: S-EPMC3783571 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.

Piao Lin L Fang Yong-Hu YH Parikh Kishan K Ryan John J JJ Toth Peter T PT Archer Stephen L SL

Journal of molecular medicine (Berlin, Germany) 20130621 10

<h4>Unlabelled</h4>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 mech ...[more]

PMID: 23794090

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Project description:The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of β-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease.

Dataset Information

Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.

Publications

Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.

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