{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:50:14Z","timestamp":1788313814547,"version":"build-2803163510"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,4,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Recent accumulating evidence suggests that toll\u2010like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              A rat model of monocrotaline\u2010induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline\u2010exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and\n              <jats:italic>interleukin\u20106<\/jats:italic>\n              mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline\u2010exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days \u22123 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF\u2010\u03baB activation and\n              <jats:italic>interleukin\u20106<\/jats:italic>\n              mRNA levels to a similar extent. In the short\u2010term reversal protocol, E646 treatment (days 14\u201317 after monocrotaline injection) almost normalized NF\u2010\u03baB activation and\n              <jats:italic>interleukin\u20106<\/jats:italic>\n              mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14\u201324 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline\u2010exposed rats.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF\u2010\u03baB\u2012IL\u20106 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.019247","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T20:21:00Z","timestamp":1624306860000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Chronic Inhibition of Toll\u2010Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats"],"prefix":"10.1161","volume":"10","author":[{"given":"Tomohito","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Medical Sciences Kyushu University Fukuoka Japan"},{"name":"Division of Cardiovascular Medicine Research Institute of Angiocardiology Faculty of Medical Sciences Kyushu University Fukuoka 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