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

ABSTRACT

Introduction: 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.

KEYWORDS:

• Anaplerosis
• glutamine
• pulmonary hypertension
• vascular
• glutamine metabolism

Article Highlights

• Increased lung glutamine consumption is observed in diverse models of pulmonary hypertension (PH), as well as in human instances of PH.

• In PH, glutamine metabolism is rewired to sustain pulmonary vascular cells hyperproliferation.

• Glutamine is converted to glutamate to feed the TCA cycle through increased glutaminase (GLS) expression.

• A number of PH triggers increase GLS expression in pulmonary vascular cells.

• Targeting GLS pharmacologically ameliorates PH in rodent models of PH.

• Pathways of glutamine metabolism provide novel therapeutic entry points for PH intervention strategies.

This box summarizes key points contained in the article.

Declaration of interest

S.Y.C. has served as a consultant for Zogenix, Vivus, Aerpio, and United Therapeutics; S.Y.C. is a director, officer, and shareholder in Numa Therapeutics; S.Y.C. holds research grants from Actelion and Pfizer. S.Y.C. and T.B. have filed patent applications regarding the targeting of metabolism in pulmonary hypertension. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have received funding from the American Heart Association [18EIA33900027], the U.S. Department of Health and Human Services, National Institutes of Health [HL 122596, HL 138437, R01 HL124021 UH2 TR002073] and the SILAB Foundation and the French National Research Agency ANR-18-CE14-0025