The molecular rationale for therapeutic targeting of glutamine metabolism in pulmonary hypertension

Pulmonary hypertension (PH) is a deadly enigmatic disease with increasing prevalence. Cellular pathologic hallmarks of PH are driven at least partly by metabolic rewiring, but details are just emerging. The discovery that vascular matrix stiffening can mechanically activate the glutaminase (GLS) enzyme and serve as a pathogenic mechanism of PH has advanced our understanding of the complex role of glutamine in PH. It has also offered a novel therapeutic target for development as a next-generation drug for this disease. Area covered: This review discusses the cellular contribution of glutamine metabolism to PH together with the possible therapeutic application of pharmacologic GLS inhibitors in this disease. Expert opinion: Despite advances in our understanding of glutamine metabolism in PH, questions remain unanswered regarding the development of therapies targeting glutamine in PH. The comprehensive mechanisms by which glutamine metabolism rewiring influences pulmonary vascular cell behavior to drive PH are incompletely understood. Because glutamine metabolism exhibits a variety of functions in organ repair and homeostasis, a better understanding of the overall risk-benefit ratio of these strategies with long-term follow-up is needed. This knowledge should pave the way for the design of new strategies to prevent and hopefully even regress PH.