Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH) in adults. An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). In order to better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary over-circulation. Consistent with PAH in adults, PASMCs derived from 4-week old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and TCA cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ ratios observed in shunt PASMCs. Consistent with these findings, pharmacologic inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyper-proliferation is observed early in the setting of pulmonary over-circulation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1 or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.
- pulmonary overcirculation
- oxygen consumption
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology