Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension

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.

Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

“…While the piperlongumine parent drug has minimal toxicity to normal, nontransformed cells, its derivatives have displayed low levels of reversible liver and kidney toxicity when administered systemically ( 60 ). Given the presence of ascites in some BRD2889-dosed rats, future therapeutic development of BRD2889 should assess for toxicity closely and may benefit from localized delivery to the lung, as we have described recently with poly(lactic-co-glycolic) acid (PLGA) microparticles ( 61 ), to avoid any putative systemic side effects. In addition, future work to integrate EDDY-CTRP-PH with a structural analytic pipeline would be appealing to define potential biophysical mechanisms by which modifications of piperlongumine can be mapped to downstream pathway rewiring.…”

Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases

“…Verteporfin, for example, is a classic YAP inhibitor and autophagy inhibitor that disrupts the YAP-TEAD interaction and induces apoptosis [ 142 , 143 , 144 ]. Studies have shown that the targeted inhibition of the YAP/TAZ through the lung-specific and controlled release of verteporfin ameliorates pulmonary hypertension in rats [ 145 ]. Gap19, a Cx43 mimetic peptide, has also been shown to target YAP signaling in reactive astrocytes after an intracerebral hemorrhage injury to reduce the expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, and MCP1), increase anti-inflammatory cytokines (IL-4 and IL-10), and increase the neuronal cell survival.…”

Endothelial Senescence: A New Age in Pulmonary Hypertension

“…124 For example, inhibition of GLS1 (glutaminase 1) serves as a senolytic by abrogating the compensatory upregulation of glutaminolysis in response to lysosomal dysfunction 125 ; separately, pharmacological targeting of inappropriate glutaminolysis prevents PH development in preclinical models. [126][127][128]…”