RGD Reference Report - Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension. - Rat Genome Database

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

Authors: Piao, Lin  Fang, Yong-Hu  Parikh, Kishan  Ryan, John J  Toth, Peter T  Archer, Stephen L 
Citation: Piao L, etal., J Mol Med (Berl). 2013 Oct;91(10):1185-97. doi: 10.1007/s00109-013-1064-7. Epub 2013 Jun 21.
RGD ID: 151361111
Pubmed: PMID:23794090   (View Abstract at PubMed)
PMCID: PMC3783571   (View Article at PubMed Central)
DOI: DOI:10.1007/s00109-013-1064-7   (Journal Full-text)


UNLABELLED: 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.
KEY MESSAGE: 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary hypertension  IEP 151361111protein:increased expression:myocytes plasma membrane and right ventricleRGD 
pulmonary hypertension  ISOSLC1A5 (Homo sapiens)151361111; 151361111protein:increased expression:myocytes plasma membrane and right ventricleRGD 
Right Ventricular Hypertrophy  ISOMe1 (Rattus norvegicus)151361111; 151361111mRNA:increased expression:right ventricleRGD 
Right Ventricular Hypertrophy  ISOMe2 (Rattus norvegicus)151361111; 151361111mRNA:increased expression:right and right ventriclesRGD 
Right Ventricular Hypertrophy  IEP 151361111mRNA:increased expression:right ventricleRGD 
Right Ventricular Hypertrophy  IEP 151361111mRNA:increased expression:right and right ventriclesRGD 
Right Ventricular Hypertrophy  ISOSlc1a5 (Rattus norvegicus)151361111; 151361111mRNA:increased expression:right ventricleRGD 
Right Ventricular Hypertrophy  ISOSlc7a5 (Rattus norvegicus)151361111; 151361111mRNA:increased expression:right and left ventriclesRGD 
Right Ventricular Hypertrophy  IEP 151361111mRNA:increased expression:right ventricleRGD 
Right Ventricular Hypertrophy  IEP 151361111mRNA:increased expression:right and left ventriclesRGD 

Objects Annotated

Genes (Rattus norvegicus)
Me1  (malic enzyme 1)
Me2  (malic enzyme 2)
Slc1a5  (solute carrier family 1 member 5)
Slc7a5  (solute carrier family 7 member 5)

Genes (Mus musculus)
Me1  (malic enzyme 1, NADP(+)-dependent, cytosolic)
Me2  (malic enzyme 2, NAD(+)-dependent, mitochondrial)
Slc1a5  (solute carrier family 1 (neutral amino acid transporter), member 5)
Slc7a5  (solute carrier family 7 (cationic amino acid transporter, y+ system), member 5)

Genes (Homo sapiens)
ME1  (malic enzyme 1)
ME2  (malic enzyme 2)
SLC1A5  (solute carrier family 1 member 5)
SLC7A5  (solute carrier family 7 member 5)


Additional Information