GLS1 immune blockade reduces PAH indications in rat model
Heart function measures, heart right side blood pressure improved
Blocking GLS1, an enzyme that drives pro-inflammatory immune macrophages, reduces the signs and symptoms of pulmonary arterial hypertension (PAH) in rats, a study reports.
“This study offers a fresh outlook upon understanding the role of macrophages in PAH and provides experimental evidence in developing targeted therapeutic strategies,” the researchers wrote. The study, “Inhibition of glutaminase 1 reduces M1 macrophage polarization to protect against monocrotaline-induced pulmonary arterial hypertension,” was published in Immunology Letters.
In PAH, an influx of immune cells and sustained local inflammatory responses contribute to the narrowing of the pulmonary arteries, the blood vessels that pass through the lungs. This restricts blood flow, drives up blood pressure, and makes it harder for the right heart to pump blood, which leads to right heart failure.
Macrophages are a type of immune cell involved in such inflammatory responses. They are classified as pro-inflammatory M1 cells that drive immune responses or anti-inflammatory M2 cells that promote healing. An imbalance in M1 and M2 function can exacerbate inflammatory responses and vascular narrowing.
Glutamine is an amino acid, that is, a protein building block. But it’s also broken down by enzymes called glutaminases (GLS) to be used as an energy source in cells, including macrophages. In fact, recent studies suggest glutamine metabolism helps regulate the transition of M1/M2 macrophages, but the exact role of glutamine metabolism in macrophages in PAH isn’t clear.
Modulating GLS1 in PAH
Researchers in China investigated the role of glutaminase type 1, or GLS1, in PAH patients and the effect of blocking the enzyme in a rat model of PAH.
The researchers examined two datasets from the publicly available GEO database, which houses information on gene expression, or activity. Both datasets showed the expression of the gene that encodes GLS1 was significantly higher in the lung tissue of PAH patients than healthy people.
Likewise, blood samples collected from PAH patients showed a marked increase in GLS1 expression in monocytes, the immune cells that mature into macrophages. Moreover, PAH patients had significantly elevated levels of glutamine and its metabolite glutamate than healthy controls. Consistent with these findings, rats with chemically induced PAH also had elevated GLS1 gene and protein expression in lung tissues, particularly in lung macrophages, over non-PAH animals.
The researchers then tested the impact of BPTES, a commonly used GLS1 inhibitor, on PAH rats. A week after PAH was induced, the rats received abdominal injections of BPTES (5 mg/kg) once daily for three weeks.
The treatment reduced high blood pressure in the right side of the heart and improved various measures of heart function. A lung tissue analysis revealed thickening of the pulmonary arterial walls in PAH rats, which BPTES alleviated. The treatment also reduced the muscularization rate of pulmonary arterioles, the abnormal process that leads to blood vessel narrowing.
BPTES also decreased markers of M1 and M2 macrophages, which were elevated in untreated PAH rats, and also significantly suppressed the secretion of pro-inflammatory signaling proteins, or cytokines, while restoring glutamine and glutamate levels to normal.
“These data suggest that BPTES regulates glutamine metabolism through modulation of GLS1, thereby exerting its therapeutic effects on PAH,” wrote the researchers, who also found a significant positive correlation between GLS1 and M1 macrophages in the lung tissue of PAH patients.
When immune cells were induced into an inflammatory state, BPTES significantly reduced M1 macrophage markers without affecting M2 markers, blocked the release of cytokines, and restored glutamine metabolism. BPTES also decreased the proliferation and migration of pulmonary arterial smooth muscle cells, which contribute to vessel wall narrowing.
“BPTES effectively attenuates the abnormally increased glutamine metabolism in PAH rats by inhibiting GLS1, thereby alleviating [blood flow] abnormalities, improving right ventricular function, as well as reducing vascular [thickening],” the researchers wrote.
About the Author
