{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T08:44:45Z","timestamp":1771058685138,"version":"3.50.1"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2011,9,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Ischemia\/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Here, we report that rat cardiac allograft ischemia\/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA\/Rho-associated protein kinase activation and endothelial cell\u2013endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1\u03b1, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia\/reperfusion injury\u2013induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with\n              <jats:italic>N<\/jats:italic>\n              -nitro-\n              <jats:sc>l<\/jats:sc>\n              -arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-\u03b21 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-\u03b21\u2013induced microvascular endothelial-to-mesenchymal transition.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia\/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.110.005249","type":"journal-article","created":{"date-parts":[[2011,8,16]],"date-time":"2011-08-16T04:48:27Z","timestamp":1313470107000},"page":"1138-1150","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":71,"title":["Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia\/Reperfusion Injury and Chronic Rejection Through Microvascular Protection"],"prefix":"10.1161","volume":"124","author":[{"given":"Raimo","family":"Tuuminen","sequence":"first","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simo","family":"Syrj\u00e4l\u00e4","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer","family":"Krebs","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikko A.I.","family":"Ker\u00e4nen","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katri","family":"Koli","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Usama","family":"Abo-Ramadan","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pertti J.","family":"Neuvonen","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jussi M.","family":"Tikkanen","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antti I.","family":"Nyk\u00e4nen","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl B.","family":"Lemstr\u00f6m","sequence":"additional","affiliation":[{"name":"From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2005.01228.x"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc5001.100796"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.711911"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2007.02.018"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200420702"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00361.2004"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000080981.90718.EB"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1420.016"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.09.003"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1911"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1613"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2009.01.007"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00177.2003"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070102"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2022"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2007.11.004"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.813311"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2005.02.009"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000043241.32523.ee"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.145.2.347"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21375"},{"key":"e_1_3_4_23_2","first-page":"H2547","article-title":"Permeability-related changes revealed at endothelial cell borders in inflamed venules by lectin binding","volume":"271","author":"Thurston G","year":"1996","unstructured":"Thurston G, Baluk P, Hirata A, McDonald DM . 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