Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation

• Published in: American journal of physiology. Heart and circulatory physiology 2016-10, Vol.311 (4), p.H944-H957
• Main Authors: Boehme, Jason, Sun, Xutong, Tormos, Kathryn V, Gong, Wenhui, Kellner, Manuela, Datar, Sanjeev A, Kameny, Rebecca Johnson, Yuan, Jason X-J, Raff, Gary W, Fineman, Jeffrey R, Black, Stephen M, Maltepe, Emin
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Call for Papers; Cardiovascular disease; Cell Proliferation; Cells, Cultured; Children & youth; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Flow Cytometry; Fluorescent Antibody Technique; Glycolysis; Hypertension; Hypertension, Pulmonary - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Membrane Potential, Mitochondrial; Metabolism; Metabolomics; Mitochondria - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; NADPH Oxidases - metabolism; Oxygen; Oxygen Consumption; Pentose Phosphate Pathway; Pulmonary Artery - cytology; Pulmonary Artery - metabolism; Pulmonary Circulation; Reactive Oxygen Species - metabolism; Sheep; Sheep, Domestic; Superoxides - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00040.2016

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). 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 overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-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 tricarboxylic acid (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, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation 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.