title: Repetitive hypoglycemia increases circulating adrenaline level with resultant worsening of intimal thickening after vascular injury in male Goto-Kakizaki rat carotid artery.
abstract: 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 α1 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.
authors.affiliation: Department of Metabolism & Endocrinology (E.Y., T.M., Y.O., K.A., H.G., C.O., A.K., Y.H., H.W.), Center for Molecular Diabetology (T.M., H.W), Sportology Center (R.K., H.W.), Center for Therapeutic Innovations in Diabetes (H.W.), Center for Beta Cell Biology and Regeneration (Y.F., H.W.), Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Yasunari
authors.forename: Tomoya
authors.initials: T
authors.lastname: Mita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Osonoi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Azuma
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Goto
authors.forename: Chie
authors.initials: C
authors.lastname: Ohmura
authors.forename: Akio
authors.initials: A
authors.lastname: Kanazawa
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Kawamori
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects*; D020212:Carotid Artery Injuries / Q000473:pathology* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004837:Epinephrine / Q000097:blood*; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D058426:Neointima / Q000139:chemically induced*; D051381:Rats; D017539:Tunica Intima / Q000187:drug effects*
chemical_list: D007328:Insulin; D004837:Epinephrine