{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:17:26Z","timestamp":1791206246819,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,3,9]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Nitric oxide synthase uncoupling occurs under conditions of oxidative stress modifying the enzyme's function so it generates superoxide rather than nitric oxide. Nitric oxide synthase uncoupling occurs with chronic pressure overload, and both are ameliorated by exogenous tetrahydrobiopterin (\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4)\u2014a cofactor required for normal nitric oxide synthase function\u2014supporting a pathophysiological link. Genetically augmenting\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 synthesis in endothelial cells fails to replicate this benefit, indicating that other cell types dominate the effects of exogenous\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 administration. We tested whether the primary cellular target of\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 is the cardiomyocyte or whether other novel mechanisms are invoked.\n            <\/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              Mice with cardiomyocyte\u2010specific overexpression of\n              <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>\n              cyclohydrolase 1 (\n              <jats:styled-content style=\"fixed-case\">mGCH<\/jats:styled-content>\n              1) and wild\u2010type littermates underwent transverse aortic constriction. The\n              <jats:styled-content style=\"fixed-case\">mGCH<\/jats:styled-content>\n              1 mice had markedly increased myocardial\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 and, unlike wild type, maintained nitric oxide synthase coupling after transverse aortic constriction; however, the transverse aortic constriction\u2013induced abnormalities in cardiac morphology and function were similar in both groups. In contrast, exogenous\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 supplementation improved transverse aortic constricted hearts in both groups, suppressed multiple inflammatory cytokines, and attenuated infiltration of inflammatory macrophages into the heart early after transverse aortic constriction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 protection against adverse remodeling in hypertrophic cardiac disease is not driven by its prevention of myocardial nitric oxide synthase uncoupling, as presumed previously. Instead, benefits from exogenous\n              <jats:styled-content style=\"fixed-case\">BH<\/jats:styled-content>\n              4 are mediated by a protective effect coupled to suppression of inflammatory pathways and myocardial macrophage infiltration.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.116.003208","type":"journal-article","created":{"date-parts":[[2016,3,22]],"date-time":"2016-03-22T03:54:46Z","timestamp":1458618886000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Tetrahydrobiopterin Protects Against Hypertrophic Heart Disease Independent of Myocardial Nitric Oxide Synthase Coupling"],"prefix":"10.1161","volume":"5","author":[{"given":"Toru","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, 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