{
    "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\u00a0days. When given orotracheally to the rats weekly for 3\u00a0weeks, 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.",
    "authors": [
        {
            "affiliation": "Department of Chemical and Petroleum Engineering University of Pittsburgh PA.\nBiological Design Graduate Program School for the Engineering of Matter, Transport, and Energy Arizona State University Tempe AZ.\nChemical Engineering School for the Engineering of Matter, Transport, and Energy Arizona State University Tempe AZ.",
            "firstname": "Abhinav P",
            "initials": "AP",
            "lastname": "Acharya"
        },
        {
            "affiliation": "Center for Pulmonary Vascular Biology and Medicine Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute Division of Cardiology Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Ying",
            "initials": "Y",
            "lastname": "Tang"
        },
        {
            "affiliation": "Universit\u00e9 C\u00f4te d'AzurCentre national de la recherche scientifique (CNRS) Bienvenue \u00e0 l'Institut de Pharmacologie Mol\u00e9culaire et Cellulaire (IPMC) Valbonne France.",
            "firstname": "Thomas",
            "initials": "T",
            "lastname": "Bertero"
        },
        {
            "affiliation": "Center for Pulmonary Vascular Biology and Medicine Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute Division of Cardiology Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Yi-Yin",
            "initials": "YY",
            "lastname": "Tai"
        },
        {
            "affiliation": "Center for Pulmonary Vascular Biology and Medicine Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute Division of Cardiology Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Lloyd D",
            "initials": "LD",
            "lastname": "Harvey"
        },
        {
            "affiliation": "Center for Pulmonary Vascular Biology and Medicine Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute Division of Cardiology Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Chen-Shan C",
            "initials": "CC",
            "lastname": "Woodcock"
        },
        {
            "affiliation": "Center for Pulmonary Vascular Biology and Medicine Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute Division of Cardiology Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Wei",
            "initials": "W",
            "lastname": "Sun"
        },
        {
            "affiliation": "Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Ricardo",
            "initials": "R",
            "lastname": "Pineda"
        },
        {
            "affiliation": "Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Nilay",
            "initials": "N",
            "lastname": "Mitash"
        },
        {
            "affiliation": "Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Melanie",
            "initials": "M",
            "lastname": "K\u00f6nigshoff"
        },
        {
            "affiliation": "Department of Chemical and Petroleum Engineering University of Pittsburgh PA.\nDepartment of Immunology University of Pittsburgh School of Medicine PA.\nDepartment of Bioengineering University of Pittsburgh PA.\nDepartment of Pharmaceutical Sciences University of Pittsburgh PA.\nDepartment of Ophthalmology University of Pittsburgh PA.\nMcGowan Institute for Regenerative Medicine University of Pittsburgh PA.",
            "firstname": "Steven R",
            "initials": "SR",
            "lastname": "Little"
        },
        {
            "affiliation": "Center for Pulmonary Vascular Biology and Medicine Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute Division of Cardiology Department of Medicine University of Pittsburgh School of Medicine PA.",
            "firstname": "Stephen Y",
            "initials": "SY",
            "lastname": "Chan"
        }
    ],
    "conclusions": null,
    "copyrights": null,
    "doi": "10.1161/JAHA.120.019091\n10.1016/j.yjmcc.2007.09.006\n10.1172/JCI86387\n10.1161/CIRCULATIONAHA.117.029930\n10.1016/j.celrep.2015.09.049\n10.1164/rccm.201510-2003OC\n10.1152/ajplung.00173.2017\n10.1038/nature10137\n10.1172/JCI74773\n10.1097/FJC.0b013e3181f9ea8d\n10.1183/09031936.00183214\n10.1165/rcmb.2019-0276TR\n10.1016/j.ejphar.2016.06.057\n10.20982/tqmp.14.4.p242\n10.1056/NEJMra040291\n10.1164/rccm.201606-1226PP\n10.1055/s-0033-1356494\n10.1126/scitranslmed.aao4583\n10.1007/s40256-015-0125-4\n10.1161/CIRCULATIONAHA.112.000765\n10.1183/16000617.0094-2017\n10.1086/688059\n10.1016/S0142-9612(00)00115-0\n10.1016/j.biomaterials.2009.04.032\n10.1016/j.clim.2015.04.013\n10.1039/C5TB01754H\n10.1038/s41598-017-17869-y\n10.1126/sciadv.1601556\n10.1152/ajplung.00300.2014\n10.1165/rcmb.2017-0238OC\n10.3390/cancers10050137\n10.1038/nm.4407",
    "journal": "Journal of the American Heart Association",
    "keywords": [
        "mechanotransduction",
        "metabolism",
        "nanoparticle",
        "pulmonary hypertension",
        "therapy"
    ],
    "methods": null,
    "publication_date": "2021-06-01",
    "pubmed_id": "34056915\n17950310\n27548520\n29444988\n26565914\n27119551\n28642262\n26909890\n21654799\n24960162\n20881610\n25929950\n31991090\n27375078\n15459304\n27627135\n24037637\n29070699\n26016608\n23403476\n29263174\n27683610\n11055295\n19477505\n25937032\n26985393\n29235530\n28435870\n25502501\n29019707\n29734788\n28967920",
    "results": null,
    "title": "Simultaneous Pharmacologic Inhibition of Yes-Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic-co-Glycolic) Acid-Encapsulated Microparticles Improves Pulmonary Hypertension.",
    "xml": "<Element 'PubmedArticle' at 0x7885046eb650>"
}