title: The effect of insulin to decrease neointimal growth after arterial injury is endothelial nitric oxide synthase-dependent.
abstract: In vitro, insulin has mitogenic effects on vascular smooth muscle cells (VSMC) but also has protective effects on endothelial cells by stimulating nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) expression. Furthermore, NOS inhibition attenuates the effect of insulin to inhibit VSMC migration in vitro. Using an in vivo model, we have previously shown that insulin decreases neointimal growth and cell migration and increases re-endothelialization after arterial injury in normal rats. Since insulin can stimulate NOS, and NO can decrease neointimal growth, we hypothesized that NOS, and more specifically eNOS was required for the effects of insulin in vivo. Rats were given subcutaneous insulin implants (3 U/day) alone or with the NOS inhibitor l-NAME (2 mg kg(-1) day(-1)) 3 days before arterial (carotid or aortic) balloon catheter injury. Insulin decreased both neointimal area (P < 0.01) and cell migration (P < 0.01), and increased re-endothelialization (P < 0.05). All of these effects were prevented by the co-administration of l-NAME. Insulin was found to decrease inducible NOS expression (P < 0.05) but increase eNOS phosphorylation (P < 0.05). These changes were also translated at the functional level where insulin improved endothelial-dependent vasorelaxation. To further study the NOS isoform involved in insulin action, s.c. insulin (0.1 U/day) was given to wild-type and eNOS knockout mice. We found that insulin was effective at decreasing neointimal formation in wild-type mice after wire injury of the femoral artery, whereas this effect of insulin was absent in eNOS knockout mice. These results show that the vasculoprotective effect of insulin after arterial injury is mediated by an eNOS-dependent mechanism.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: June
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.affiliation: Children's Hospital Research Institute of Manitoba, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Pereira
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Dalvi
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Hangjun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Diabetes, Metabolism and Endocrinology, Showa University, Shinagawa, Tokyo 142-0064, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Kaleida Health, Buffalo, NY 14209, USA.
authors.forename: Husam
authors.initials: H
authors.lastname: Ghanim
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Tumiati
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: I George
authors.initials: IG
authors.lastname: Fantus
authors.affiliation: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Bendeck
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Kaleida Health, Buffalo, NY 14209, USA.
authors.forename: Paresh
authors.initials: P
authors.lastname: Dandona
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
authors.affiliation: Children's Hospital Research Institute of Manitoba, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: adria.giacca@utoronto.ca.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D062326:Re-Epithelialization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004343:Drug Implants; D004791:Enzyme Inhibitors; D007328:Insulin; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat
keywords: Angioplasty; Endothelial nitric oxide synthase; Insulin; Neointima; Re-endothelialization