Metabolic derangement may facilitate cell proliferation in PAH

By Eleanor McDermid, Senior medwireNews Reporter

An enzyme that facilitates modification of proteins via a glucose metabolism pathway may promote cell proliferation in the lung tissue of patients with idiopathic pulmonary arterial hypertension (IPAH), say researchers.

The hexosamine biosynthetic pathway (HBP) usually accounts for only a small proportion of glucose metabolism, but Raed Dweik (Cleveland Clinic, Ohio, USA) and team found this pathway to be upregulated in lung tissue from eight patients with IPAH compared with that from eight controls without the condition.

Its rate-limiting enzyme, glutamine:fructose-6-phosphate aminotransferase-1, was increased more than threefold in lung tissue and nearly twofold in isolated pulmonary artery smooth muscle cells (PASMCs) from the IPAH patients.

The product of this pathway, the sugar nucleotide UDP-N-acetyl-glucosamine (GlcNAc), was significantly less abundant in IPAH tissue than control tissue. But this further implicated activation of the HBP pathway, because GlcNAc is involved in protein glycosylation, and O-linked GlcNAc protein modification was significantly increased in IPAH lung tissue and PASMCs relative to control tissue. And the enzyme for this process, O-linked GlcNAc transferase (OGT), was significantly upregulated.

Previous research has shown that OGT also activates the cell cycle master regulator host cell factor (HCF)-1. In line with this, Dweik et al found that knockdown of the gene encoding OGT in isolated PASMCs resulted in reduced proliferation, bringing the proliferation of IPAH PASMCs down to the level of control PASMCs. And there was a corresponding reduction in levels of HCF-1 cleavage products.

Similar to studies in cancer cells, the findings suggest that proliferating cells in IPAH patients are primarily using aerobic glycolysis to metabolise oxygen, because this pathway provides not only the energy but also the “building blocks” for rapid proliferation.

Based on previous cancer studies, the researchers examined OGT levels in 86 IPAH patients’ red blood cells (RBC), finding them to be significantly increased, as was O-linked GlcNAc protein modification.

RBC OGT levels were related to clinical severity, being higher in patients with worse right heart stroke volume and 6-minute walk distance and with more severe New York Heart Association functional class. Furthermore, patients with high OGT levels (OGT/beta-actin ratio ≥0.396) were 3.71-fold more likely to be hospitalised, undergo lung transplant or die during a median follow-up of 24.5 months.

The team proposes a model for IPAH in which the HBP is upregulated in proliferating cells, leading to OGT utilising UDP-GlcNAc to cleave HCF-1, resulting in increased PASMC proliferation.

“This model establishes a regulatory role for OGT in IPAH, sheds a new light on our understanding of the disease pathobiology, and provides opportunities to design novel therapeutic strategies for IPAH”, they conclude in Circulation.

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