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

Jason Boehme, Xutong Sun, Kathryn V. Tormos, Wenhui Gong, Manuela Kellner, Sanjeev A. Datar, Rebecca Johnson Kameny, Jason X.J. Yuan, Gary W. Raff, Jeffrey R. Fineman, Stephen Matthew Black, Emin Maltepe

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H944-H957
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume311
Issue number4
DOIs
StatePublished - Jan 1 2016

Fingerprint

Pulmonary Hypertension
Pulmonary Artery
Smooth Muscle Myocytes
NADPH Oxidase
Lung
NADP
Heart Diseases
Pentose Phosphate Pathway
Citric Acid Cycle
Metabolome
Oxygen Consumption
Membrane Potentials
Blood Vessels
Lactic Acid
Sheep
Cell Proliferation
Pharmacology
Growth

Keywords

  • Glycolysis
  • Mitochondria
  • Oxygen consumption
  • Pulmonary overcirculation
  • ROS

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation. / 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 Matthew; Maltepe, Emin.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 311, No. 4, 01.01.2016, p. H944-H957.

Research output: Contribution to journalArticle

Boehme, J, Sun, X, Tormos, KV, Gong, W, Kellner, M, Datar, SA, Kameny, RJ, Yuan, JXJ, Raff, GW, Fineman, JR, Black, SM & Maltepe, E 2016, 'Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation', American Journal of Physiology - Heart and Circulatory Physiology, vol. 311, no. 4, pp. H944-H957. https://doi.org/10.1152/ajpheart.00040.2016
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 Matthew ; Maltepe, Emin. / Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 311, No. 4. pp. H944-H957.
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