{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:46:31Z","timestamp":1787028391976,"version":"build-2736575974"},"reference-count":28,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2014,10,27]],"date-time":"2014-10-27T00:00:00Z","timestamp":1414368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent studies suggest that hyperhomocysteinemia (HHcy) increases collagen type I accumulation in rat vascular adventitia after balloon injury and that Angiotensin II (Ang II) induces collagen synthesis in vascular adventitial fibroblasts. Reports also indicate that Ang II type1 receptor (AT1R) activation, mediated by homocysteine (Hcy) may contribute to collagen type 1 expression in mouse aortic endothelial cells. However, little is known about the possible mechanisms behind the relationship between Hcy and AT1R in adventitial remodeling. Thus, we investigated whether HHcy induces collagen accumulation via activation of AT1R in the adventitia. Male Sprague-Dawley (SD) rats were randomly divided into a control group and a 1% l-methionine-induced HHcy group. Balloon injury was performed after 12 experimental weeks and animals were sacrificed at 7, 14, and  28 days after injury. Collagen deposition and AT1R expression was measured with Western blot. Serum Hcy, adventitial collagen, and AT1R levels were higher in the HHcy group compared with the control group. Hcy time-dependently induced collagen type 1 and AT1R expression, with the highest induction observed at 48 h. Also, we observed that the AT1R blocker, valsartan, attenuated collagen type 1 and AT1R expression. HHcy exacerbates adventitial remodeling after balloon injury, and the underling mechanisms may be related to AT1R activity.<\/jats:p>","DOI":"10.3390\/ijms151119487","type":"journal-article","created":{"date-parts":[[2014,10,27]],"date-time":"2014-10-27T11:38:09Z","timestamp":1414409889000},"page":"19487-19498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Hyperhomocysteinemia Accelerates Collagen Accumulation in the Adventitia of Balloon-Injured Rat Carotid Arteries via Angiotensin II Type 1 Receptor"],"prefix":"10.3390","volume":"15","author":[{"given":"Dan","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Cardiology, Peking University People's Hospital, No. 11 Xizhimen South Street,  Xicheng District of Beijing, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning-Ling","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University People's Hospital, No. 11 Xizhimen South Street,  Xicheng District of Beijing, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1161\/ATVBAHA.106.137851","article-title":"Topological determinants and consequences of adventitial responses to arterial wall injury","volume":"27","author":"Michel","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1161\/01.RES.0000059306.71961.ED","article-title":"Coordinate control of proliferation and migration by the p27kip1\/cyclin-dependent kinase\/retinoblastoma pathway in vascular smooth muscle cells and fibroblasts","volume":"92","author":"Andres","year":"2003","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.bbrc.2005.10.207","article-title":"NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation","volume":"339","author":"Shen","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1161\/01.CIR.95.4.997","article-title":"Origin of extracellular matrix synthesis during coronary repair","volume":"95","author":"Shi","year":"1997","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"363","DOI":"10.7326\/0003-4819-131-5-199909070-00008","article-title":"Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence","volume":"131","author":"Eikelboom","year":"1999","journal-title":"Ann. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1055\/s-2000-8096","article-title":"Mild hyperhomocysteinemia is an independent risk factor of arterial vascular disease","volume":"26","author":"Boers","year":"2000","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1161\/hq0901.096582","article-title":"Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in apoe-deficient mice","volume":"21","author":"Zhou","year":"2001","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1172\/JCI10588","article-title":"Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model","volume":"107","author":"Hofmann","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1055\/s-0037-1613962","article-title":"Homocysteine as a risk factor for restenosis after coronary angioplasty","volume":"84","author":"Morita","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1053\/euhj.2001.2962","article-title":"Association of plasma homocysteine with restenosis after percutaneous coronary angioplasty","volume":"23","author":"Schnyder","year":"2002","journal-title":"Eur. Heart J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/S0002-8703(03)00518-0","article-title":"Restenosis in intervened coronaries with hyperhomocysteinemia (rich)","volume":"146","author":"Kojoglanian","year":"2003","journal-title":"Am. Heart J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1097\/00029330-200811020-00011","article-title":"Diet-induced hyperhomocysteinemia exacerbates vascular reverse remodeling of balloon-injured arteries in rat","volume":"121","author":"Guo","year":"2008","journal-title":"Chin. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1161\/01.CIR.103.1.133","article-title":"Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury","volume":"103","author":"Morita","year":"2001","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1515\/CCLM.2007.354","article-title":"Synergism between at1 receptor and hyperhomocysteinemia during vascular remodeling","volume":"45","author":"Sen","year":"2007","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1080\/08037050310001057","article-title":"Angiotensin AT1\/AT2 receptors: Regulation, signalling and function","volume":"12","author":"Kaschina","year":"2003","journal-title":"Blood Press."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3317\/jraas.2006.039","article-title":"The angiotensin type 1 receptor antagonist valsartan attenuates pathological ventricular hypertrophy induced by hyperhomocysteinemia in rats","volume":"7","author":"Kassab","year":"2006","journal-title":"J. Renin Angiotensin Aldosterone Syst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1136\/hrt.2003.020701","article-title":"Lack of association between baseline plasma homocysteine concentrations and restenosis rates after a first elective percutaneous coronary intervention without stenting","volume":"90","author":"Wong","year":"2004","journal-title":"Heart"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/sj.jhh.1001983","article-title":"Mild hyperhomocysteinaemia is associated with increased aortic stiffness in general population","volume":"20","author":"Mayer","year":"2006","journal-title":"J. Hum. Hypertens."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.cardiores.2003.09.028","article-title":"Increased collagen turnover is only partly associated with collagen fiber deposition in the arterial response to injury","volume":"61","author":"Sluijter","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jtbi.2003.08.004","article-title":"A computational model for collagen fibre remodelling in the arterial wall","volume":"226","author":"Driessen","year":"2004","journal-title":"J. Theor. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1161\/01.HYP.37.4.1047","article-title":"Theodore cooper lecture: Tissue angiotensin and pathobiology of vascular disease: A unifying hypothesis","volume":"37","author":"Dzau","year":"2001","journal-title":"Hypertension"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ha, Y.M., Park, E.J., Kang, Y.J., Park, S.W., Kim, H.J., and Chang, K.C. (2014). Valsartan independent of at receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of EGR-1 through activation of AMPK in diabetic conditions. J. Cell. Mol. Med.","DOI":"10.1111\/jcmm.12354"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1161\/CIRCRESAHA.112.270520","article-title":"Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice","volume":"111","author":"Liu","year":"2012","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.cca.2008.09.019","article-title":"Analytical performance of an enzymatic cycling method for total homocysteine measurement","volume":"399","author":"Jin","year":"2009","journal-title":"Clin. Chim. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1161\/CIRCULATIONAHA.113.001725","article-title":"Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization","volume":"128","author":"Kang","year":"2013","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.atherosclerosis.2012.07.020","article-title":"Inhibition of neointimal hyperplasia in the rat carotid artery injury model by a HMGB1 inhibitor","volume":"224","author":"Chen","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3346\/jkms.1999.14.5.487","article-title":"Angiotensin II stimulates proliferation of adventitial fibroblasts cultured from rat aortic explants","volume":"14","author":"Kim","year":"1999","journal-title":"J. Korean Med. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.bbrc.2004.10.014","article-title":"Adrenomedullin induces matrix metalloproteinase-2 activity in rat aortic adventitial fibroblasts","volume":"325","author":"Tsuruda","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/11\/19487\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:17:26Z","timestamp":1760217446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/11\/19487"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,27]]},"references-count":28,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2014,11]]}},"alternative-id":["ijms151119487"],"URL":"https:\/\/doi.org\/10.3390\/ijms151119487","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,27]]}}}