Simultaneous pharmacologic inhibition of yes-associated protein 1 and glutaminase 1 via inhaled poly(Lactic-co-glycolic) acid–encapsulated microparticles improves pulmonary hypertension

Abhinav P. Acharya, Ying Tang, Thomas Bertero, Yi Yin Tai, Lloyd D. Harvey, Chen Shan C. Woodcock, Wei Sun, Ricardo Pineda, Nilay Mitash, Melanie Königshoff, Steven R. Little, Stephen Y. Chan

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metab-olism. 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 stiffen-ing) 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.

Original languageEnglish (US)
Article numbere019091
JournalJournal of the American Heart Association
Volume10
Issue number12
DOIs
StatePublished - 2021

Keywords

  • Mechanotransduction
  • Metabolism
  • Nanoparticle
  • Pulmonary hypertension
  • Therapy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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