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Recently, we developed a highly specific tryptophan hydroxylase 1 inhibitor (TPHi): TPT-004. We hypothesized that repetitive nose-only inhalation of TPT-004 alleviates PAH and pulmonary vascular remodeling in the Sugen 5416\/hypoxia (SuHx) rat model. Male Sprague Dawley rats were divided into three groups: ConNx (control animals kept in room air during the study); SuHx+vehicle (rats injected with the VEGFR2 inhibitor SU5416 and then exposed to chronic hypoxia for 3 weeks, followed by 10 days recovery and subsequent 4 weeks of daily vehicle inhalations; and SuHx+TPHi (SuHx-exposed rats after recovery treated with daily inhalations of the TPH1 inhibitor, TPT-004, for 4 weeks). Closed-chest right\u2013left heart catheterization and cardiac magnetic resonance imaging were performed in spontaneously breathing rats. Histological and mRNA-sequencing analyses were performed on lungs. SuHx-exposed rats had severe PAH, right ventricle (RV) hypertrophy, and RV dilation. In comparison with SuHx-exposed rats, TPHi-treated SuHx rats had significantly lower RV systolic pressure (67.25 vs. 51.47 mm Hg; P\u2009&amp;lt;\u20090.0001), normalized RV end-systolic volume (182.6 vs. 105.1 \u03bcl; P\u2009&amp;lt;\u20090.0001), and improved RV ejection fraction by cardiac magnetic resonance imaging (47.9 vs. 66.8%; P\u2009&amp;lt;\u20090.0001). Inhaled TPT-004 did not affect left ventricular (LV) end-diastolic or systemic blood pressure. TPT-004 therapy reversed pulmonary vascular remodeling and alveolar macrophage infiltration. RNA sequencing unraveled TPHi-induced changes in pulmonary gene expression: increased cell adhesion as well as reduced cell motility and migration; suppressed extracellular matrix remodeling; modulated immune response; and suppressed pulmonary vascular remodeling by means of modulating proliferation, apoptosis, and homeostasis. Taken together, TPT-004 is an effective therapeutic PAH agent that does not cause any hemodynamic adverse effects in rodents, and thus, should be tested further towards a clinical phase 1b\/phase 2 study in patients with PAH.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0365oc","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T13:39:31Z","timestamp":1738589971000},"page":"288-298","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":7,"title":["Inhalation of the Novel Tryptophan Hydroxylase 1 Inhibitor TPT-004 Alleviates Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"73","author":[{"given":"Ekaterina","family":"Legchenko","sequence":"first","affiliation":[{"name":"Department of Pediatric Cardiology and Critical Care"},{"name":"Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Chouvarine","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology and Critical Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klea","family":"Hysko","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology and Critical Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatimunnisa","family":"Qadri","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC), Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radoslaw","family":"Wesolowski","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC), Berlin, Germany"},{"name":"Trypto Therapeutics GmbH, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Specker","sequence":"additional","affiliation":[{"name":"Trypto Therapeutics GmbH, Berlin, Germany"},{"name":"Chemical Biology Platform, Leibniz-Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP), Berlin-Buch, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Glage","sequence":"additional","affiliation":[{"name":"Pathohistological Diagnostics, Central Animal Facility, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Meier","sequence":"additional","affiliation":[{"name":"Small Animal Imaging Centre, Central Animal Facility, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Heineke","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Pohlmann","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Ramazanoglu","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bader","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC), Berlin, Germany"},{"name":"Trypto Therapeutics GmbH, Berlin, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany"},{"name":"Charit\u00e9 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"},{"name":"Institute for Biology, University of L\u00fcbeck, L\u00fcbeck, Germany; 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