Article ; Online: Simultaneous Pharmacologic Inhibition of Yes-Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic-co-Glycolic) Acid-Encapsulated Microparticles Improves Pulmonary Hypertension.
Journal of the American Heart Association
2021 Volume 10, Issue 12, Page(s) e019091
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Administration, Inhalation ; Animals ; Benzeneacetamides/administration & dosage ; Benzeneacetamides/chemistry ; Cells, Cultured ; Delayed-Action Preparations ; Disease Models, Animal ; Drug Carriers ; Drug Combinations ; Drug Compounding ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/chemistry ; Glutaminase/antagonists & inhibitors ; Glutaminase/metabolism ; Hemodynamics/drug effects ; Humans ; Hypertension, Pulmonary/chemically induced ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/physiopathology ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/metabolism ; Lung/drug effects ; Lung/metabolism ; Lung/physiopathology ; Male ; Mechanotransduction, Cellular ; Monocrotaline ; Particle Size ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Rats, Sprague-Dawley ; Thiadiazoles/administration & dosage ; Thiadiazoles/chemistry ; Time Factors ; Vascular Remodeling/drug effects ; Ventricular Function, Right/drug effects ; Verteporfin/administration & dosage ; Verteporfin/chemistry ; YAP-Signaling Proteins ; Rats |
| Chemical Substances | Benzeneacetamides ; CB-839 ; Delayed-Action Preparations ; Drug Carriers ; Drug Combinations ; Enzyme Inhibitors ; Intracellular Signaling Peptides and Proteins ; Thiadiazoles ; YAP-Signaling Proteins ; Yap1 protein, rat ; Verteporfin (0X9PA28K43) ; Polylactic Acid-Polyglycolic Acid Copolymer (1SIA8062RS) ; Monocrotaline (73077K8HYV) ; Glutaminase (EC 3.5.1.2) |
| Language | English |
| Publishing date | 2021-05-29 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2653953-6 |
| ISSN | 2047-9980 ; 2047-9980 |
| ISSN (online) | 2047-9980 |
| ISSN | 2047-9980 |
| DOI | 10.1161/JAHA.120.019091 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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