{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:41:31Z","timestamp":1788385291873,"version":"build-2803163510"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2019,7,19]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>We aimed to discover a novel drug for PAH that inhibits PASMC proliferation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole\u2013type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1\u03b1 (hypoxia-inducible factor 1\u03b1), which impairs aerobic metabolism, and \u03baB (nuclear factor-\u03baB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.315229","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T09:00:22Z","timestamp":1560502822000},"page":"309-327","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"125","author":[{"given":"Ryo","family":"Kurosawa","sequence":"first","affiliation":[{"name":"From the Department of Cardiovascular Medicine (R.K., K.S., N.K., E.A.M., M.A.H.S., J.O., T.S., S.S., M.N., K.N., S.M., H.S.), Sendai, Japan"},{"name":"Japan Society for the Promotion of Science, Tokyo, Japan (R.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimio","family":"Satoh","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine (R.K., K.S., N.K., E.A.M., M.A.H.S., J.O., T.S., S.S., M.N., K.N., S.M., H.S.), Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine (R.K., K.S., N.K., E.A.M., M.A.H.S., J.O., T.S., S.S., M.N., K.N., S.M., H.S.), Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhisa","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan (H.K., K.K., Y.M., T.D., J.A., Y.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Saigusa","sequence":"additional","affiliation":[{"name":"Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organizaition (D.S., A.U., M.Y.), Sendai, Japan"},{"name":"Department of Medical Biochemistry, Tohoku University Graduate School of Medicine (D.S., A.U., M.Y.), Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. 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