{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:10:42Z","timestamp":1789038642623,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016728","name":"Kyoto Pharmaceutical University","doi-asserted-by":"publisher","award":["16-5"],"award-info":[{"award-number":["16-5"]}],"id":[{"id":"10.13039\/100016728","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016728","name":"Kyoto Pharmaceutical University","doi-asserted-by":"publisher","award":["2022060878"],"award-info":[{"award-number":["2022060878"]}],"id":[{"id":"10.13039\/100016728","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016728","name":"Kyoto Pharmaceutical University","doi-asserted-by":"publisher","award":["22K06639"],"award-info":[{"award-number":["22K06639"]}],"id":[{"id":"10.13039\/100016728","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hoansha Foundation","award":["16-5"],"award-info":[{"award-number":["16-5"]}]},{"name":"Hoansha Foundation","award":["2022060878"],"award-info":[{"award-number":["2022060878"]}]},{"name":"Hoansha Foundation","award":["22K06639"],"award-info":[{"award-number":["22K06639"]}]},{"name":"Promotion and Mutual Aid Corporation for Private Schools of Japan","award":["16-5"],"award-info":[{"award-number":["16-5"]}]},{"name":"Promotion and Mutual Aid Corporation for Private Schools of Japan","award":["2022060878"],"award-info":[{"award-number":["2022060878"]}]},{"name":"Promotion and Mutual Aid Corporation for Private Schools of Japan","award":["22K06639"],"award-info":[{"award-number":["22K06639"]}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["16-5"],"award-info":[{"award-number":["16-5"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["2022060878"],"award-info":[{"award-number":["2022060878"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["22K06639"],"award-info":[{"award-number":["22K06639"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["16-5"],"award-info":[{"award-number":["16-5"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["2022060878"],"award-info":[{"award-number":["2022060878"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["22K06639"],"award-info":[{"award-number":["22K06639"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Secreted protein acidic rich in cysteine (SPARC), one of the extracellular matrix proteins, is highly induced during inflammation. We investigated the pathophysiological regulation and role of SPARC in vascular inflammation in a rat model of hypertension created using deoxycorticosterone acetate (DOCA, 40 mg\/kg\/week, s.c.) and salt (1% in drinking water). DOCA\u2013salt administration time-dependently increased systolic blood pressure during the 3-week treatment period, blunted endothelium-dependent vasodilation, and increased monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in the aorta. SPARC expression transiently increased until week 2 in the DOCA\u2013salt rat aorta. Interestingly, aortic SPARC levels correlated with blood pressure and the levels of MCP-1 and LOX-1 during 0\u20132 weeks. The AT1 receptor blocker, losartan, suppressed the overexpression of SPARC, and in vitro treatment with angiotensin II enhanced the production of SPARC in rat aortic endothelial cells. Exposure to recombinant SPARC protein induced overexpression of MCP-1 and LOX-1 mRNA in endothelial cells. Bioactive forms of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), excessive activation of which contributes to pathological states and overexpression of which is reported to be induced by SPARC, were increased in the DOCA\u2013salt rat aorta. These results suggest that SPARC is induced by the vascular renin\u2013angiotensin system and causes inflammation in the early stages of hypertensive vascular injury, and that activation of ADAMTS1 might be related to the proinflammatory effects of SPARC.<\/jats:p>","DOI":"10.3390\/ijms26094414","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T09:08:56Z","timestamp":1746522536000},"page":"4414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Secreted Protein Acidic and Rich in Cysteine (SPARC) Induced by the Renin\u2013Angiotensin System Causes Endothelial Inflammation in the Early Stages of Hypertensive Vascular Injury"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3860-805X","authenticated-orcid":false,"given":"Hiroe","family":"Toba","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan"},{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5799-0672","authenticated-orcid":false,"given":"Mitsushi J.","family":"Ikemoto","sequence":"additional","affiliation":[{"name":"Molecular Composite Physiology Research Group, Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan"},{"name":"Laboratory of Exercise Biochemistry and Neuroendocrinology, Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba 305-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Kobara","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-8168","authenticated-orcid":false,"given":"Denan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-4477","authenticated-orcid":false,"given":"Shinji","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Nakata","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Poznyak, A.V., Sadykhov, N.K., Kartuesov, A.G., Borisov, E.E., Melnichenko, A.A., Grechko, A.V., and Orekhov, A.N. (2022). Hypertension as a risk factor for atherosclerosis: Cardiovascular risk assessment. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.959285"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1097\/00005344-199322004-00002","article-title":"The role of endothelium in cardiovascular homeostasis and diseases","volume":"22","author":"Rubanyi","year":"1993","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_3","first-page":"136","article-title":"The endothelium in health and in cardiovascular disease","volume":"16","year":"1997","journal-title":"P. R. Health Sci. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1161\/CIRCRESAHA.115.307611","article-title":"Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease","volume":"118","author":"Herrington","year":"2016","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0945-053X(00)00105-0","article-title":"SPARC, a matricellular protein: At the crossroads of cell-matrix","volume":"19","author":"Brekken","year":"2000","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14831","DOI":"10.1016\/S0021-9258(18)98545-5","article-title":"Extracellular proteins that modulate cell-matrix interactions. SPARC, tenascin, and thrombospondin","volume":"266","author":"Sage","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"C972","DOI":"10.1152\/ajpcell.00402.2014","article-title":"Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization","volume":"308","author":"Toba","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ng, Y.L., Klopcic, B., Lloyd, F., Forrest, C., Greene, W., and Lawrance, I.C. (2013). Secreted protein acidic and rich in cysteine (SPARC) exacerbates colonic inflammatory symptoms in dextran sodium sulphate-induced murine colitis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077575"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.2353\/ajpath.2007.061273","article-title":"Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension","volume":"171","author":"Socha","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/sj.gene.6364388","article-title":"Splenic and immune alterations of the Sparc-null mouse accompany a lack of immune response","volume":"8","author":"Rempel","year":"2007","journal-title":"Genes. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Xu, L., Ping, F., Yin, J., Xiao, X., Xiang, H., Ballantyne, C.M., Wu, H., and Li, M. (2013). Elevated plasma SPARC levels are associated with insulin resistance, dyslipidemia, and inflammation in gestational diabetes mellitus. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081615"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"174681","DOI":"10.1016\/j.ejphar.2021.174681","article-title":"Secreted protein acidic and rich in cysteine (SPARC) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) increments by the renin-angiotensin system induce renal fibrosis in deoxycorticosterone acetate-salt hypertensive rats","volume":"914","author":"Toba","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev.physiol.59.1.395","article-title":"Biological functions of angiotensin and its receptors","volume":"59","author":"Matsusaka","year":"1997","journal-title":"Annu. Rev. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/0002-8703(91)90694-D","article-title":"Resolved and unresolved issues in the prevention and treatment of coronary artery disease: A workshop consensus statement","volume":"121","author":"Dzau","year":"1991","journal-title":"Am. Heart J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E1027","DOI":"10.1152\/ajpendo.00040.2016","article-title":"Increased ADAMTS1 mediates SPARC-dependent collagen deposition in the aging myocardium","volume":"310","author":"Toba","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jphs.2025.03.010","article-title":"Suppressing SPARC gene with siRNA exerts therapeutic effects and inhibits MMP-2\/9 and ADAMTS1 overexpression in a murine model of ischemia\/reperfusion-induced acute kidney injury","volume":"158","author":"Toba","year":"2025","journal-title":"J. Pharmacol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1161\/01.ATV.18.5.842","article-title":"Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse","volume":"18","author":"Nakashima","year":"1998","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/386073a0","article-title":"An endothelial receptor for oxidized low-density lipoprotein","volume":"386","author":"Sawamura","year":"1997","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0163-7258(02)00236-X","article-title":"LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: Implications in endothelial dysfunction and atherosclerosis","volume":"95","author":"Chen","year":"2002","journal-title":"Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33471","DOI":"10.1074\/jbc.M002599200","article-title":"Characterization of METH-1\/ADAMTS1 processing reveals two distinct active forms","volume":"275","author":"Milchanowski","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/29788","article-title":"Decreased lesion formation in CCR2-\/- mice reveals a role for chemokines in the initiation of atherosclerosis","volume":"394","author":"Boring","year":"1998","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10557-011-6324-6","article-title":"The discovery of LOX-1, its ligands and clinical significance","volume":"25","author":"Yoshimoto","year":"2011","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"117390","DOI":"10.1016\/j.atherosclerosis.2023.117390","article-title":"The association of SPARC with hypertension and its function in endothelial-dependent relaxation","volume":"388","author":"Li","year":"2024","journal-title":"Atherosclerosis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1161\/CIRCULATIONAHA.121.057001","article-title":"SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension","volume":"145","author":"Veith","year":"2022","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1172\/JCI39738","article-title":"Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia\/reperfusion","volume":"119","author":"Qi","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/jcb.23015","article-title":"Identification of a sequence in the matricellular protein SPARC that interacts with the scavenger receptor stabilin-1","volume":"112","author":"Workman","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9739977","DOI":"10.1155\/2021\/9739977","article-title":"SPARC Aggravates Blood-Brain Barrier Disruption via Integrin alphaVbeta3\/MAPKs\/MMP-9 Signaling Pathway after Subarachnoid Hemorrhage","volume":"2021","author":"Okada","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_28","first-page":"R289","article-title":"Renal nerve activity and renal function during environmental stress in DOCA-NaCl rats","volume":"251","author":"Koepke","year":"1986","journal-title":"Am. J. Physiol."},{"key":"ref_29","first-page":"225","article-title":"11-Deoxycorticosterone-induced hypertension, glomerulosclerosis and renal arterial and arteriolar lesions","volume":"58","author":"Shimamura","year":"1988","journal-title":"Jpn. J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1097\/00004872-199405000-00011","article-title":"Plasma renin activity and changes in tissue angiotensin converting enzyme","volume":"12","author":"Michel","year":"1994","journal-title":"J. Hypertens."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/00004872-199501000-00017","article-title":"Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats","volume":"13","author":"Wada","year":"1995","journal-title":"J. Hypertens."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1681\/ASN.V891373","article-title":"Secreted protein acidic and rich in cysteine expression after subtotal nephrectomy and blockade of the renin-angiotensin system","volume":"8","author":"Wu","year":"1997","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ejphar.2012.01.026","article-title":"Telmisartan inhibits vascular dysfunction and inflammation via activation of peroxisome proliferator-activated receptor-gamma in subtotal nephrectomized rat","volume":"685","author":"Toba","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1159\/000355482","article-title":"Telmisartan protects against vascular dysfunction with peroxisome proliferator-activated receptor-gamma activation in hypertensive 5\/6 nephrectomized rats","volume":"92","author":"Toba","year":"2013","journal-title":"Pharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0169-6009(90)90079-U","article-title":"Circulating levels of osteonectin in normal subjects and patients with thrombocytopenia","volume":"9","author":"Malaval","year":"1990","journal-title":"Bone Miner."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/jbmr.5650020514","article-title":"Radioimmunoassay for osteonectin. Concentrations in bone, nonmineralized tissues, and blood","volume":"2","author":"Malaval","year":"1987","journal-title":"J. Bone Miner. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S1388-9842(99)00029-X","article-title":"Increased soluble platelet\/endothelial cellular adhesion molecule-1 and osteonectin levels in patients with severe congestive heart failure. Independence of disease etiology, and antecedent aspirin therapy","volume":"1","author":"Serebruany","year":"1999","journal-title":"Eur. J. Heart Fail."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13372","DOI":"10.1074\/jbc.M009737200","article-title":"Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4","volume":"276","author":"Sandy","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1161\/01.ATV.0000150045.27127.37","article-title":"Role of ADAMTS-1 in atherosclerosis: Remodeling of carotid artery, immunohistochemistry, and proteolysis of versican","volume":"25","author":"Nilsson","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1253\/jcj.27.282","article-title":"Development of a strain of spontaneously hypertensive rats","volume":"27","author":"Okamoto","year":"1963","journal-title":"Jpn. Circ. J."},{"key":"ref_41","first-page":"2173","article-title":"Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta","volume":"54","author":"Bonnier","year":"2011","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"32145","DOI":"10.1074\/jbc.274.45.32145","article-title":"SPARC regulates the expression of collagen type I and transforming growth factor-beta1 in mesangial cells","volume":"274","author":"Francki","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1038\/ki.1996.520","article-title":"SPARC is expressed in renal interstitial fibrosis and in renal vascular injury","volume":"50","author":"Pichler","year":"1996","journal-title":"Kidney Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ejphar.2011.01.043","article-title":"Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5\/6 nephrectomized rat aorta","volume":"656","author":"Toba","year":"2011","journal-title":"Eur. J. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:27:50Z","timestamp":1760030870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,6]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094414"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094414","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,6]]}}}