glutaminase and Hypertension--Pulmonary

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.

Topics: Animals; Drug Development; Enzyme Inhibitors; Glutaminase; Glutamine; Humans; Hypertension, Pulmonary; Molecular Targeted Therapy

Background Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes-associated protein 1) and transcriptional coactivator with PDZ-binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB-839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. Methods and Results We used poly(lactic-co-glycolic) acid polymer-based microparticles for delivery of verteporfin and CB-839 simultaneously to the lungs of rats suffering from monocrotaline-induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB-839 alone, displayed significant improvement across all indexes of PH. Conclusions Simultaneous, lung-specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease.

Topics: Administration, Inhalation; Animals; Benzeneacetamides; Cells, Cultured; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Drug Combinations; Drug Compounding; Enzyme Inhibitors; Glutaminase; Hemodynamics; Humans; Hypertension, Pulmonary; Intracellular Signaling Peptides and Proteins; Lung; Male; Mechanotransduction, Cellular; Monocrotaline; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Rats, Sprague-Dawley; Thiadiazoles; Time Factors; Vascular Remodeling; Ventricular Function, Right; Verteporfin; YAP-Signaling Proteins