Glucose Metabolism and Smooth Muscle Cell Proliferation in Idiopathic PAH | Journal Scan

Study Questions:

What is the relationship between glucose metabolism and smooth muscle cell (SMC) proliferation in idiopathic pulmonary arterial hypertension (IPAH)?

Methods:

Glutamine:fructose-6-phosphate aminotransferase-1 (GFAT1), the HBP rate-limiting enzyme, was increased in IPAH lung tissue (control, 8.2 ± 7.0; IPAH, 28.1 ± 12.4, p = 0.002). A similar finding was determined in IPAH pulmonary arterial SMCs (PASMCs) isolated from the lung explants (GFAT1: control, 4.1 ± 1.2; IPAH, 7.1 ± 2.0, p = 0.02). These data suggest that the activation of the HBP directly increased OGT levels and activity-triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-GlcNAc levels and abrogated PASMC proliferation. The increased proliferation observed in PAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1 (HCF-1).

Results:

Glutamine:fructose-6-phosphate aminotransferase-1 (GFAT1), the HBP rate-limiting enzyme, was increased in IPAH lung tissue (control, 8.2 ± 7.0; IPAH, 28.1 ± 12.4, p = 0.002). A similar finding was determined in IPAH pulmonary arterial smooth muscle cells (PASMCs) isolated from the lung explants (GFAT1: control, 4.1 ± 1.2; IPAH, 7.1 ± 2.0, p = 0.02). These data suggest that the activation of the HBP directly increased OGT levels and activity-triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-GlcNAc levels and abrogated PASMC proliferation. The increased proliferation observed in PAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1 (HCF-1).

Conclusions:

The authors concluded that HBP flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of HCF-1.

Perspective:

This study reports that PASMC proliferation, a major component in the pathobiology of IPAH, is directed by increased HBP flux coupled with enhanced OGT activity, causing proteolytic activation of HCF-1. These findings suggest a direct role for OGT in linking nutrient sensing of the HBP to cell cycle progression and proliferation, which may have clinical implications for a number of diseases beyond IPAH including cardiovascular disease, cancer, and diabetes. Additional research is needed to determine the systemic nature of the dysregulated metabolism in IPAH to elucidate potential novel therapies.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Lipid Metabolism, Pulmonary Hypertension

Keywords: Hypertension, Pulmonary, Cell Division, Cell Proliferation, Glucose, Glutamine, Glycosylation, Host Factor 1 Protein, Myocytes, Smooth Muscle, Neoplasms, Proteolysis, Pulmonary Artery, Transaminases


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