{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T04:02:45Z","timestamp":1746244965480,"version":"3.40.4"},"reference-count":34,"publisher":"The Endocrine Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,6,1]]},"abstract":"<jats:p>Hypoglycemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect of hypoglycemic episodes including a surge of sympathetic activity on the progression of neointima formation after vascular injury remains largely unknown. In this study, insulin was injected intraperitoneally into nonobese diabetic Goto-Kakizaki (GK) rats, once every 3 days for 4 weeks after balloon injury of carotid artery to induce hypoglycemia. Then, we evaluated balloon injury-induced neointima formation. Insulin treatment enhanced neointima formation and increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in the carotid artery. Injection of glucose with insulin prevented hypoglycemia and abrogated intimal thickening. Also, bunazosin, an \u03b11 adrenergic receptor antagonist, prevented intimal thickening and accumulation of PCNA-positive cells induced by insulin treatment despite the presence of concomitant hypoglycemia and high adrenaline levels. Incubation of cultured smooth muscle cells with adrenaline resulted in a significant increase in their proliferation and G0\/G1 to S phase progression, which was associated with activation of extracellular signal-regulated kinase, enhanced expression of cell cycle regulatory molecules such as cyclin D1, and cyclin E, and phosphorylation of retinoblastoma protein. These adrenaline-induced effects were abrogated by bunazosin. Our data indicated that increased adrenaline induced by repetitive hypoglycemia promotes intimal thickening and smooth muscle cell proliferation after endothelial denudation in GK rats.<\/jats:p>","DOI":"10.1210\/en.2013-1628","type":"journal-article","created":{"date-parts":[[2014,3,31]],"date-time":"2014-03-31T16:18:08Z","timestamp":1396282688000},"page":"2244-2253","source":"Crossref","is-referenced-by-count":12,"title":["Repetitive Hypoglycemia Increases Circulating Adrenaline Level with Resultant Worsening of Intimal Thickening After Vascular Injury in Male Goto-Kakizaki Rat Carotid Artery"],"prefix":"10.1210","volume":"155","author":[{"given":"Eisuke","family":"Yasunari","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Mita","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"},{"name":"Department of Center for Molecular Diabetology (T.M., H.W), Sportology Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Osonoi","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Azuma","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromasa","family":"Goto","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chie","family":"Ohmura","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akio","family":"Kanazawa","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuzo","family":"Kawamori","sequence":"first","affiliation":[{"name":"Department of Center (R.K., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshio","family":"Fujitani","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"},{"name":"Department of Center for Beta Cell Biology and Regeneration (Y.F., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirotaka","family":"Watada","sequence":"first","affiliation":[{"name":"Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"},{"name":"Department of Center for Molecular Diabetology (T.M., H.W), Sportology Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"},{"name":"Department of Center (R.K., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"},{"name":"Department of Center for Therapeutic Innovations in Diabetes (H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"},{"name":"Department of Center for Beta Cell Biology and Regeneration (Y.F., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113\u20138421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071612511289100_B1","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.jacc.2006.09.045","article-title":"Coronary heart disease in patients with diabetes: part II: recent advances in coronary revascularization","volume":"49","author":"Berry","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2020071612511289100_B2","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/0735-1097(95)00496-3","article-title":"Potential mechanisms promoting restenosis in diabetic patients","volume":"27","author":"Aronson","year":"1996","journal-title":"J Am Coll Cardiol"},{"key":"2020071612511289100_B3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/ccd.23185","article-title":"Prognostic role of preprocedural glucose levels on short- and long-term outcome in patients undergoing percutaneous coronary revascularization","volume":"80","author":"Nusca","year":"2012","journal-title":"Catheter Cardiovasc Interv"},{"key":"2020071612511289100_B4","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/dmrr.865","article-title":"Vascular disease and diabetes: is hypoglycaemia an aggravating factor?","volume":"24","author":"Wright","year":"2008","journal-title":"Diabetes Metab Res Rev"},{"key":"2020071612511289100_B5","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.2337\/diacare.26.4.1176","article-title":"Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use","volume":"26","author":"Leese","year":"2003","journal-title":"Diabetes Care"},{"key":"2020071612511289100_B6","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00592-013-0473-y","article-title":"Emergency hospitalizations for severe hypoglycaemia in patients with type 2 diabetes","volume":"50","author":"Di Cianni","year":"2013","journal-title":"Acta Diabetol"},{"key":"2020071612511289100_B7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1365-2362.1983.tb00061.x","article-title":"Peripheral blood cell changes in response to acute hypoglycaemia in man","volume":"13","author":"Frier","year":"1983","journal-title":"Eur J Clin Invest"},{"key":"2020071612511289100_B8","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1464-5491.1990.tb01432.x","article-title":"Leucocyte mobilization and release of neutrophil elastase following acute insulin-induced hypoglycaemia in normal humans","volume":"7","author":"Collier","year":"1990","journal-title":"Diabet Med"},{"key":"2020071612511289100_B9","doi-asserted-by":"crossref","first-page":"861","DOI":"10.2337\/diacare.23.6.861","article-title":"Insulin-induced hypoglycemia induces a rise in C-reactive protein","volume":"23","author":"Galloway","year":"2000","journal-title":"Diabetes Care"},{"key":"2020071612511289100_B10","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.2337\/dc09-9032","article-title":"Hyperglycemic crises in adult patients with diabetes","volume":"32","author":"Kitabchi","year":"2009","journal-title":"Diabetes Care"},{"key":"2020071612511289100_B11","first-page":"109","article-title":"Responses of peripheral blood cells to acute insulin-induced hypoglycaemia in humans: effect of alpha-adrenergic blockade","volume":"26","author":"Fisher","year":"1992","journal-title":"Horm Metab Res Suppl"},{"key":"2020071612511289100_B12","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1007\/s00125-011-2141-5","article-title":"Repetitive hypoglycaemia increases serum adrenaline and induces monocyte adhesion to the endothelium in rat thoracic aorta","volume":"54","author":"Jin","year":"2011","journal-title":"Diabetologia"},{"key":"2020071612511289100_B13","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1161\/hh2101.098379","article-title":"Trophic effect of norepinephrine on arterial intima-media and adventitia is augmented by injury and mediated by different alpha1-adrenoceptor subtypes","volume":"89","author":"Zhang","year":"2001","journal-title":"Circ Res"},{"key":"2020071612511289100_B14","doi-asserted-by":"crossref","first-page":"H1577","DOI":"10.1152\/ajpheart.00218.2002","article-title":"Alpha(1)-adrenoceptor stimulation directly induces growth of vascular wall in vivo","volume":"283","author":"Erami","year":"2002","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612511289100_B15","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S0022-3565(24)29401-5","article-title":"Expression of alpha-adrenoceptor subtypes by smooth muscle cells and adventitial fibroblasts in rat aorta and in cell culture","volume":"298","author":"Faber","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"2020071612511289100_B16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0022-3565(24)34864-5","article-title":"alpha1-Adrenergic receptor stimulation of mitogenesis in human vascular smooth muscle cells: role of tyrosine protein kinases and calcium in activation of mitogen-activated protein kinase","volume":"290","author":"Hu","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"2020071612511289100_B17","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.2337\/db09-1694","article-title":"Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4","volume":"59","author":"Arakawa","year":"2010","journal-title":"Diabetes"},{"key":"2020071612511289100_B18","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.bbrc.2010.04.031","article-title":"Impact of insulin resistance on enhanced monocyte adhesion to endothelial cells and atherosclerogenesis independent of LDL cholesterol level","volume":"395","author":"Mita","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612511289100_B19","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1210\/en.2012-1855","article-title":"Anagliptin, a DPP-4 Inhibitor, Suppresses Proliferation of Vascular Smooth Muscles and Monocyte Inflammatory Reaction and Attenuates Atherosclerosis in Male apo E-Deficient Mice","volume":"154","author":"Ervinna","year":"2013","journal-title":"Endocrinology"},{"key":"2020071612511289100_B20","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1254\/jjp.59.255","article-title":"Effect of manidipine on balloon catheter-induced arterial smooth muscle cell proliferation in spontaneously diabetic GK rats","volume":"59","author":"Odaka","year":"1992","journal-title":"Jpn J Pharmacol"},{"key":"2020071612511289100_B21","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/1475-2840-11-150","article-title":"Detecting DNA synthesis of neointimal formation after catheter balloon injury in GK and in Wistar rats: using 5-ethynyl-2\u2032-deoxyuridine","volume":"11","author":"Guo","year":"2012","journal-title":"Cardiovasc Diabetol"},{"key":"2020071612511289100_B22","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.vph.2007.06.009","article-title":"Epothilone D, a microtubule-stabilizing compound, inhibits neointimal hyperplasia after rat carotid artery injury by cell cycle arrest via regulation of G1-checkpoint proteins","volume":"47","author":"Kim","year":"2007","journal-title":"Vascul Pharmacol"},{"key":"2020071612511289100_B23","doi-asserted-by":"crossref","first-page":"701","DOI":"10.2337\/db08-1230","article-title":"Effects of intensive therapy and antecedent hypoglycemia on counterregulatory responses to hypoglycemia in type 2 diabetes","volume":"58","author":"Davis","year":"2009","journal-title":"Diabetes"},{"key":"2020071612511289100_B24","doi-asserted-by":"crossref","first-page":"H2364","DOI":"10.1152\/ajpheart.00858.2001","article-title":"Different alpha-adrenoceptors mediate migration of vascular smooth muscle cells and adventitial fibroblasts in vitro","volume":"282","author":"Zhang","year":"2002","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612511289100_B25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/1097-0045(2000)45:9+<29::AID-PROS7>3.0.CO;2-Z","article-title":"Alpha(1)-adrenoceptors (alpha(1)-AR) and vascular smooth muscle cell growth","volume":"9","author":"Hoffman","year":"2000","journal-title":"Prostate Suppl"},{"key":"2020071612511289100_B26","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1097\/00005344-199604000-00009","article-title":"Regulation of protein synthesis by alpha 1-adrenergic receptor subtypes in cultured rabbit aortic vascular smooth muscle cells","volume":"27","author":"Siwik","year":"1996","journal-title":"J Cardiovasc Pharmacol"},{"key":"2020071612511289100_B27","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1161\/01.CIR.0000012750.08480.55","article-title":"Cardiovascular influences of alpha1b-adrenergic receptor defect in mice","volume":"105","author":"Vecchione","year":"2002","journal-title":"Circulation"},{"key":"2020071612511289100_B28","first-page":"75","article-title":"Alpha 1-receptor antagonists urapidil and prazosin inhibit neointima formation in rat carotid artery induced by balloon catheter injury","volume":"86","author":"Fingerle","year":"1991","journal-title":"Basic Res Cardiol"},{"key":"2020071612511289100_B29","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/S0008-6363(95)00216-2","article-title":"Doxazosin blocks the angiotensin II-induced smooth muscle cell DNA synthesis in the media, but not in the neointima of the rat carotid artery after balloon injury","volume":"31","author":"van Kleef","year":"1996","journal-title":"Cardiovasc Res"},{"key":"2020071612511289100_B30","doi-asserted-by":"crossref","first-page":"H385","DOI":"10.1152\/ajpheart.00658.2002","article-title":"Systemic alpha 1A-adrenoceptor antagonist inhibits neointimal growth after balloon injury of rat carotid artery","volume":"284","author":"Teeters","year":"2003","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612511289100_B31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1291\/hypres.27.129","article-title":"Combined treatment with an AT1 receptor blocker and angiotensin converting enzyme inhibitor has an additive effect on inhibiting neointima formation via improvement of nitric oxide production and suppression of oxidative stress","volume":"27","author":"Yagi","year":"2004","journal-title":"Hypertens Res"},{"key":"2020071612511289100_B32","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1161\/HYPERTENSIONAHA.110.149781","article-title":"Nifedipine inhibits vascular smooth muscle cell dedifferentiation via downregulation of Akt signaling","volume":"56","author":"Kaimoto","year":"2010","journal-title":"Hypertension"},{"key":"2020071612511289100_B33","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.2337\/dc09-2082","article-title":"Hypoglycemia, diabetes, and cardiovascular events","volume":"33","author":"Desouza","year":"2010","journal-title":"Diabetes Care"},{"key":"2020071612511289100_B34","doi-asserted-by":"crossref","first-page":"5157","DOI":"10.1210\/en.2004-0728","article-title":"Differential regulation of the cell cycle by alpha1-adrenergic receptor subtypes","volume":"145","author":"Gonzalez-Cabrera","year":"2004","journal-title":"Endocrinology"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/155\/6\/2244\/10826123\/endo2244.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/155\/6\/2244\/10826123\/endo2244.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T06:27:33Z","timestamp":1746167253000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/155\/6\/2244\/2422359"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,1]]},"references-count":34,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2014,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2013-1628","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"type":"print","value":"0013-7227"},{"type":"electronic","value":"1945-7170"}],"subject":[],"published":{"date-parts":[[2014,6,1]]}}}