{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:14:53Z","timestamp":1783422893172,"version":"3.54.6"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Atherosclerosis and aortic aneurysms often co-exist, attributed to common risk factors predisposing to development of these severe vascular disorders.  The apoE null mice represent a classical model of atherosclerosis.  It has been shown that endothelial nitric oxide synthase (eNOS) is modestly uncoupled in apoE null mice at baseline to contribute to oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Notably, we have previously demonstrated marked activation of eNOS in its uncoupled state in angiotensin II (Ang II) infused hph-1 mice, which triggers formation of abdominal aortic aneurysm (AAA), representing the first evidence documenting a direct causal role of eNOS uncoupling in AAA formation that can be reversed by recoupling of eNOS with oral administration of folic acid (FA) or plasmid-mediated overexpression of dihydrofolate reductase (DHFR). In the present study, hph-1(hyperphenylalaninemia-1)\/apoE double mutant mice were created in-house, and exposed to Ang II infusion (0.7 mg\/kg\/day) for 2 weeks alongside apoE null mice, during which formation of AAA was monitored by echo determination of abdominal aortic size on weekly basis and post-mortem inspection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Indeed, although AAA formation was not significantly different between apoE and hph-1\/apoE mice, there were significantly more atherosclerotic lesions formed in hph-1\/apoE double mutant mice. These data indicate that AAA forms consequent to a certain extent of eNOS uncoupling activity. By contrast, worsened eNOS uncoupling activity is still associated with deteriorated atherogenesis in hph-1\/apoE double mutant mice.  In addition, oral FA administration or overexpression of DHFR substantially alleviated excessive atherosclerosis and AAA formation in apoE null mice and hph-1\/apoE double mutant mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings seem to establish that targeting DHFR to fully restore eNOS function or to fully recouple eNOS into its native coupled state, can be employed as a novel and robust therapeutic strategy to alleviate advanced atherosclerosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1864121","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T04:25:19Z","timestamp":1782793519000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Attenuation of advanced atherosclerosis and aortic aneurysm in hph-1\/apoE DKO mice by folic acid and DHFR overexpression"],"prefix":"10.3389","volume":"17","author":[{"given":"Yixuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin Lung","family":"Siu","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanli","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B34","doi-asserted-by":"publisher","first-page":"14786","DOI":"10.1038\/s41598-018-32100-2","article-title":"Tobacco smoking and the risk of abdominal aortic aneurysm: A systematic review and meta-analysis of prospective studies","volume":"8","author":"Aune","year":"2018","journal-title":"Sci. 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