Table 2.
Increased glycolysis and hypoxia-inducible factor (HIF) expression in pulmonary hypertension
| Sources | Parameters | References |
|---|---|---|
| Human data | ||
| Pulmonary arterial endothelial cells (PAEC) in vitro | Hypoxia-inducible factor (HIF) presence in nuclear extract by Western blot analyses, ↑5-3H-glucose to 3H2O, ↑13C-fructose bisphosphate from 13C-glucose [↑proximate glycolysis pathway intermediates], ↑Lactate by spectrophotometry, ↑Hepatocyte growth factor (HGF) and stromal-derived factor (SDF)-1 by ELISA |
(10, 11, 16, 26) |
| Pulmonary artery smooth muscle cells (PASMC) in vitro |
↑13C-pyruvate and 13C-lactate from 13C-glucose [↑ glucose uptake and utilization], ↑Enolase (ENO)1 by Western blot analyses |
(16, 35) |
| Lung | HIF presence by immunohistochemistry, ↑18Fluorodeoxyglucose (FDG) uptake, ↑6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3 and lactate dehydrogenase (LDH)B by Western blot analyses, ↑HGF and SDF-1 by immunohistochemistry, ↑PFKFB2 and LDHB by gene microarray analyses, ↑Glucose to sorbitol, fructose, and fructose 6-phosphate, ↓Fructose 1,6-bisphosphate (FBP), 3-phosphoglycerate (3-PGA), and phosphoenolpyruvate (PEP) by metabolomics, ↓Glucose-6-phosphatase catalytic subunit 3 (G6PC3) by Western blot analyses, immunohistochemistry, and gene microarray analyses |
(10, 11, 15, 26, 31, 34, 36, 37) |
| Small pulmonary arteries | HIF presence by immunofluorescence | (14, 15) |
| Right ventricle | HIF presence in nuclei of cardiomyocytes by immunohistochemistry, ↑18FDG uptake, ↑Glycolytic gene, e.g. Hexokinase (HK)2 and solute carrier family 2 member 3 (SLC2A3), expression by microarray analyses |
(29, 31, 38, 39, 47, 48) |
| Animal models | ||
| Shunt lambsa | ||
| Lung | ↑Lactate/pyruvate ratio by spectrophotometry, | (40, 45) |
| Fawn hooded ratsb | ||
| PASMC | HIF presence by immunofluorescence | (14, 15) |
| Small rat pulmonary arteries | HIF presence by Western blot analyses | (14, 15) |
| Hypoxia/Sugen ratsc | ||
| Lung |
↑ENO, ↑PFKFB3 mRNA by qRT-PCR, protein by Western blot analyses, and activity by F-2,6-P2 assay |
(35, 37, 41) |
| Right ventricle | ↑HK1 and phosphofructokinase (PFKM) by gene microarray analyses | (41) |
| Monocrotaline (MCT) ratsd | ||
| Lung | ↑ Glucose transporter (GLUT)1 and LDHA mRNA by qRT-PCR and protein by Western blot | (44) |
| Right ventricle |
↑18FDG uptake, ↑GLUT1 protein expression by Western blot analyses, ↑GLUT1, HK2 and LDHA mRNA by qRT-PCR |
(42–44) |
| Liver | ↑Metabolic fluxes including glucose, lactate, and pyruvate in liver perfusion | (55) |
a
Shunt lambs, with pulmonary hypertension secondary to increased pulmonary blood flow with surgically created heart defect;
b
Fawn hooded rats, a spontaneously pulmonary hypertensive strain with a hereditary bleeding tendency due to a genetic defect in platelet aggregation;
c
Hypoxia/Sugen rats, with hypoxia or sugen-induced pulmonary hypertension;
d
MCT rats, a maladaptive model (heart failure model) combined with PAH and right ventricular hypertrophy induced by MCT