Abstract 16628: The Uncoupling Protein 2: The New Metabolic Switch in Human Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is characterized by vascular lesions and obstructions of the distal pulmonary arteries (PA). This phenotype is associated with metabolic unbalance known as Warburg effect (enhanced glycolysis/glucose oxidation). In cancer, this metabolic signature accounts for cell proliferation and resistance to apoptosis, through the activation of the hypoxic inducible factor-1 (HIF-1). While a similar metabolic and proliferative/anti-apoptotic phenotype has been described in human PAH, the origin of the Warburg effect remains unknown. Uncoupling proteins UCPs are mitochondrial proteins that short circuit the electrochemical gradient created by the mitochondrial respiratory chain by sustaining an inducible proton conductance. Nonetheless due to their varied tissue distribution and regulation distinct roles have been identified. For instance, UCP2 differs from other UCPs by not exclusively conducting protons, but also pyruvate, which could explain the Warburg effect. We hypothesized that UCP2 upregulation in PAH will trigger Warburg effect, promoting HIF-1 activation and thus PAH-PASMC proliferation and resistance to apoptosis.
Methods/results: Using human lung tissues (8 control vs 8 PAH) and cultured PASMC from patients with (n=3) or without (n=5) PAH we showed that UCP2 is increased (qRT-PCR, western blot) in distal PAs and in PAH-PASMC (p<0.05). Using UCP2 siRNA, we showed that by decreasing mitochondrial pyruvate concentration (p<0.05), UCP2 accounts for the development of the Warburg effect (increased lactate production; p<0.05 and decreased pyruvate dehydrogenase activity p<0.05) in PAH-PASMC. The UCP2-dependent increases in Warburg effect decreases the Krebs cycle by product alpha ketoglutarate (p<0.05) triggering HIF-1 activation (p<0.05). Using UCP2 siRNAs, we showed that the UCP2-dependent activation of HIF-1 promotes PAH-PASMC proliferation (Ki67) and decreases apoptosis (TUNEL). In vivo, we showed that nebulized UCP2 siRNA reverses monocrotaline induced PAH in rats and that UCP2 KO mice are resistant to PAH.
Conclusion: we demonstrated for the first time that UCP2 is etiologically implicated in PAH and is at the origin of the Warburg effect.
- © 2011 by American Heart Association, Inc.