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

Autor: Stephen M. Black, Emin Maltepe, Manuela Kellner, Gary W. Raff, Xutong Sun, Kathryn V. Tormos, Sanjeev A. Datar, Jeffrey R. Fineman, Jason Boehme, Wenhui Gong, Rebecca J Kameny, Jason X.-J. Yuan
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Pulmonary Circulation
Heart disease
Physiology
Fluorescent Antibody Technique
030204 cardiovascular system & hematology
Mitochondrion
Muscle
Smooth
Vascular
Pentose Phosphate Pathway
0302 clinical medicine
Superoxides
Glycolysis
Cells
Cultured
Membrane Potential
Mitochondrial
NADPH oxidase
ROS
glycolysis
Flow Cytometry
oxygen consumption
Mitochondria
mitochondria
Call for Papers
Cardiology and Cardiovascular Medicine
medicine.medical_specialty
Hypertension
Pulmonary
Blotting
Western
Myocytes
Smooth Muscle
Biology
Pentose phosphate pathway
Pulmonary Artery
03 medical and health sciences
Oxygen Consumption
Physiology (medical)
medicine.artery
Internal medicine
medicine
Animals
Metabolomics
Sheep
Domestic
Cell Proliferation
Sheep
Electron Spin Resonance Spectroscopy
NADPH Oxidases
Metabolism
medicine.disease
Hypoxia-Inducible Factor 1
alpha Subunit
Disease Models
Animal
030104 developmental biology
Endocrinology
Pulmonary artery
biology.protein
pulmonary overcirculation
Reactive Oxygen Species
Flux (metabolism)
Zdroj: Boehme, J; Sun, X; Tormos, KV; Gong, W; Kellner, M; Datar, SA; et al.(2016). Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation. American Journal of Physiology-Heart and Circulatory Physiology, 311(4), H944-H957. doi: 10.1152/ajpheart.00040.2016. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/7zg1543m
DOI: 10.1152/ajpheart.00040.2016.
Popis: © 2016 the American Physiological Society.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.
Databáze: OpenAIRE
Externí odkaz: