{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T19:13:30Z","timestamp":1781550810125,"version":"3.54.5"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Marfan syndrome is an inherited disorder caused by\n                      <jats:italic toggle=\"yes\">FBN1<\/jats:italic>\n                      gene mutations, which can lead to thoracic aortic aneurysm and dissection. Selective AT\n                      <jats:sub>1<\/jats:sub>\n                      (angiotensin II type 1) receptor blockade is a preventive option against Marfan syndrome aortopathy, and recent clinical studies demonstrated that the inhibitory effect of an ARB (AT\n                      <jats:sub>1<\/jats:sub>\n                      receptor blocker) losartan on aortic aneurysm growth is equivalent to that of \u03b2-blockers. At present, several ARBs are clinically available, and they have drug-specific differences in pharmacological properties. Especially, inverse agonism of ARBs has potential benefits for cardiovascular protection, but its impact on Marfan syndrome aortopathy remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Candesartan-7H is a candesartan derivative that lacks the carboxyl group critical for inverse agonist activity and works as a neutral antagonist for the AT\n                      <jats:sub>1<\/jats:sub>\n                      receptor. Candesartan cilexetil (1 mg\/kg per day), candesartan-7H (1 or 20 mg\/kg per day), or vehicle was administered to\n                      <jats:italic toggle=\"yes\">Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice, and aortic dilatation was analyzed using echocardiography, histological staining, and in situ MMP (matrix metalloproteinase) assay. Activation of TGF-\u03b2 (transforming growth factor \u03b2) signaling and mechanosensitive signaling was studied using Western blot and immunohistochemical analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Candesartan cilexetil (1 mg\/kg per day) and candesartan-7H (20 mg\/kg per day) lowered blood pressures equally in\n                      <jats:italic toggle=\"yes\">Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice. Progressive dilatation of the aorta in association with aortic wall thickening, degeneration of elastic fibers, deposition of collagen, MMP activation, and TGF-\u03b2 signaling activation in\n                      <jats:italic toggle=\"yes\">Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice was significantly suppressed by treatment with candesartan cilexetil (1 mg\/kg per day), but not by candesartan-7H, even at 20 mg\/kg per day. In addition, candesartan cilexetil, but not candesartan-7H, suppressed activation of mechanosensitive signaling involving focal adhesion kinase, p38 mitogen-activated protein kinase, and early growth response-1 in the ascending aorta of\n                      <jats:italic toggle=\"yes\">Fbn1<\/jats:italic>\n                      <jats:sup>C1041G\/+<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our findings support a crucial role of inverse agonist activity of ARB for the prevention of mechanical stress-induced AT\n                      <jats:sub>1<\/jats:sub>\n                      receptor activation and aortic aneurysm progression in Marfan syndrome mice.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.322646","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T10:00:39Z","timestamp":1762423239000},"page":"132-144","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Inverse Agonist Activity of Angiotensin II Receptor Blocker Is Crucial for Prevention of Progressive Aortic Dilatation in Marfan Syndrome"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6615-6196","authenticated-orcid":true,"given":"Hiroki","family":"Yagi","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine (H.Y., H.A., Q.L., M.U., H.K., R.M., A.S., S.O., T.U., A.S.-K., K.U., N.T.), Graduate School of Medicine, the University of Tokyo, Japan."},{"name":"Marfan Syndrome Center (H.Y., N.T.), the University of Tokyo Hospital, Tokyo, 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