{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:06:34Z","timestamp":1790795194650,"version":"4.1.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,10,26]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>A number of epidemiological studies have suggested an association of hyperhomocysteinemia (HHcy) and abdominal aortic aneurysm (AAA), but discrepancies exist. In addition, we lack direct evidence supporting a causal role.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>We determined the association and contribution of HHcy to AAA formation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              We first performed a meta-analysis of studies involving 1489 subjects and found a strong association of HHcy and AAA (odds ratio, 7.39). Next, we used angiotensin II\u2013infused male apolipoprotein E\u2013deficient mice and tested whether HHcy contributes to AAA pathogenesis. Homocysteine (Hcy) supplement (1.8 g\/L) in drinking water resulted in mild HHcy. Intriguingly, HHcy greatly increased the incidence of angiotensin II\u2013induced AAA and aortic dissection in apolipoprotein E\u2013deficient mice (vehicle versus Hcy: 50% versus 100%;\n              <jats:italic>P&lt;0.05<\/jats:italic>\n              ). Histology indicated HHcy markedly exaggerated aortic adventitial inflammation. Increased levels of proinflammatory interleukin-6 and monocyte chemoattractant protein-1 were preferentially colocalized within adventitial fibroblasts in HHcy plus angiotensin II mice, which suggested the importance of adventitial fibroblasts activation in Hcy-aggravated AAA. Hcy sequentially stimulated adventitial fibroblasts transformation into myofibroblasts, secretion of interleukin-6 and monocyte chemoattractant protein-1, and consequent recruitment of monocytes\/macrophages to adventitial fibroblasts, which was abolished by the NADPH oxidase inhibitor diphenyliodonium. NADPH oxidase 4, but not other homologs of NADPH oxidase, was significantly upregulated by Hcy in adventitial fibroblasts, whereas NADPH oxidase 4 small interfering RNA silencing diminished Hcy-induced adventitial fibroblasts activation. Finally, folic acid supplement (0.071 \u03bcg\/g per day) markedly reduced HHcy-aggravated angiotensin II\u2013induced AAA formation in apolipoprotein E\u2013deficient mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>HHcy may aggravate AAA formation at least partially via activating adventitial fibroblast NADPH oxidase 4.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.112.270520","type":"journal-article","created":{"date-parts":[[2012,8,22]],"date-time":"2012-08-22T05:52:04Z","timestamp":1345614724000},"page":"1261-1273","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":145,"title":["Hyperhomocysteinemia Exaggerates Adventitial Inflammation and Angiotensin II\u2212Induced Abdominal Aortic Aneurysm in Mice"],"prefix":"10.1161","volume":"111","author":[{"given":"Ziyi","family":"Liu","sequence":"first","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhi","family":"Luo","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqian","family":"Huang","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kongyang","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Feng","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsheng","family":"Xie","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingang","family":"Zheng","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyan","family":"Zhan","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingbo","family":"Xu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Kong","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. China (J.Z.); Department of Epidemiology and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Z.L, H.L., Y.H., B.L., K.M., J.F., Y.Z., W.K., X.W.); Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, P. R. China (J.X.); Department of Cardiology, China-Japan Friendship Hospital, Beijing, P. R. 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