{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:21:12Z","timestamp":1790684472877,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,11,16]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl\u20104 hydroxylase 2)\/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive.<\/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\n                      <jats:italic>\n                        Egln1\n                        <jats:sup>Tie2Cre<\/jats:sup>\n                      <\/jats:italic>\n                      (\n                      <jats:italic>Tie2<\/jats:italic>\n                      \u2010Cre\u2010mediated deletion of\n                      <jats:italic>Egln1<\/jats:italic>\n                      [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen\u2010induced endothelial\n                      <jats:italic>Egln1<\/jats:italic>\n                      deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of\n                      <jats:italic>Hif2a<\/jats:italic>\n                      but not\n                      <jats:italic>Hif1a<\/jats:italic>\n                      in\n                      <jats:italic>\n                        Egln1\n                        <jats:sup>Tie2Cre<\/jats:sup>\n                      <\/jats:italic>\n                      mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF\u20102\u03b1 as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF\u20102\u03b1 attenuated cardiac hypertrophy and fibrosis in\n                      <jats:italic>\n                        Egln1\n                        <jats:sup>Tie2Cre<\/jats:sup>\n                      <\/jats:italic>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF\u20102\u03b1\u2013dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2\/HIF\u20102\u03b1 signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.121.022077","type":"journal-article","created":{"date-parts":[[2021,11,6]],"date-time":"2021-11-06T05:05:18Z","timestamp":1636175118000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Loss of Endothelial Hypoxia Inducible Factor\u2010Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis"],"prefix":"10.1161","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-7923","authenticated-orcid":false,"given":"Zhiyu","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Internal Medicine College of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"},{"name":"Translational Cardiovascular Research CenterCollege of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-3851","authenticated-orcid":false,"given":"Jianding","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Forensic Pathology Zhongshan School of MedicineSun Yat\u2010sen University Guangzhou Guangdong China"},{"name":"Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat\u2010sen University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"},{"name":"Translational Cardiovascular Research CenterCollege of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"},{"name":"Translational Cardiovascular Research CenterCollege of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anlin","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"},{"name":"Department of Environmental Health Science and Center of Translational Science Florida International University Port Saint Lucie FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine\u2013PhoenixUniversity of Arizona Phoenix AZ"},{"name":"Department of Environmental Health Science and Center of Translational Science Florida International University Port Saint Lucie FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"An","sequence":"additional","affiliation":[{"name":"Department of Biosystems Engineering Department of Epidemiology and Biostatistics University of Arizona Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Cardiovascular Research Laboratories David Geffen School of MedicineUniversity of California, Los Angeles Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0852-0767","authenticated-orcid":false,"given":"Yibin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Cardiovascular Research Laboratories David Geffen School of MedicineUniversity of California, Los Angeles Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4961-732X","authenticated-orcid":false,"given":"Maggie M.","family":"Zhu","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology Stanley Manne Children\u2019s Research InstituteAnn &amp; Robert H. 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