{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:01:16Z","timestamp":1772164876016,"version":"3.50.1"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,11,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Tetrahydrobiopterin is a cofactor of endothelial NO synthase (\n                      <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\n                      ), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of tetrahydrobiopterin on\n                      <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\n                      uncoupling and congenital heart defects (\n                      <jats:styled-content style=\"fixed-case\">CHD<\/jats:styled-content>\n                      s) induced by pregestational diabetes mellitus in mice.\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                      Adult female mice were induced to pregestational diabetes mellitus by streptozotocin and bred with normal male mice to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation.\n                      <jats:styled-content style=\"fixed-case\">CHD<\/jats:styled-content>\n                      s were identified by histological analysis. Cell proliferation,\n                      <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\n                      dimerization, and reactive oxygen species production were assessed in the fetal heart. Pregestational diabetes mellitus results in a spectrum of\n                      <jats:styled-content style=\"fixed-case\">CHD<\/jats:styled-content>\n                      s in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of\n                      <jats:styled-content style=\"fixed-case\">CHD<\/jats:styled-content>\n                      s from 59% to 27%, and major abnormalities, such as atrioventricular septal defect and double\u2010outlet right ventricle, were absent in the sapropterin\u2010treated group. Lineage tracing reveals that pregestational diabetes mellitus results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes mellitus were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased\n                      <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\n                      dimerization and lowered reactive oxygen species levels in the fetal heart.\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                      Sapropterin treatment in the diabetic mothers improves\n                      <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\n                      coupling, increases cell proliferation, and prevents the development of\n                      <jats:styled-content style=\"fixed-case\">CHD<\/jats:styled-content>\n                      s in the offspring. Thus, sapropterin may have therapeutic potential in preventing\n                      <jats:styled-content style=\"fixed-case\">CHD<\/jats:styled-content>\n                      s in pregestational diabetes mellitus.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.118.009624","type":"journal-article","created":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T05:02:02Z","timestamp":1540270922000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes Mellitus in Mice"],"prefix":"10.1161","volume":"7","author":[{"given":"Anish","family":"Engineer","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry University of Western Ontario London Ontario 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