title: Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery.
abstract: We tested the hypothesis that hyperinsulinemia induces the suppression of protein tyrosine phosphatase 1B (PTP1B) function, leading to enhanced PDGF receptor (PDGFR) signaling and neointimal hyperplasia. Rats were implanted with insulin-releasing pellets or sham pellets. Blood glucose levels, insulin levels, food and water intake, body weights, and blood pressures were measured. Neointimal hyperplasia was assessed by computerized morphometry 14 days after carotid balloon injury. PTP1B protein expression in injured arteries was determined via Western blot analysis, whereas PTP1B activity was determined via an immunophosphatase assay. Serum insulin levels were two- to threefold greater in hyperinsulinemic rats, whereas systolic blood pressures, food and water intake, serum triglyceride levels, plasma cortisol levels, and urinary catecholamine levels were not affected. Fourteen days after injury, neointima-to-media area ratios were 0.89 +/- 0.23 and 1.35 +/- 0.22 in control and hyperinsulinemic rats, respectively (P < 0.01). PTP1B protein levels and total PTP1B activity in injured carotid arteries from the insulin-treated group were significantly decreased 7 or 14 days after injury, whereas PTP1B specific activity was decreased only 14 days after injury. These findings were associated with decreased PTP1B mRNA levels and increased PDGFR tyrosyl phosphorylation in insulin-treated rats. These observations support the hypothesis that hyperinsulinemia induces the suppression of PTP1B function, leading to enhanced PDGFR signaling and neointimal hyperplasia.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA. qpu@physio1.utmem.edu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Pu
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Chang
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Aviv
authors.initials: A
authors.lastname: Hassid
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000473:pathology*; D002395:Catecholamines / Q000097:blood; D002404:Catheterization; D006854:Hydrocortisone / Q000097:blood; D006946:Hyperinsulinism / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D002395:Catecholamines; D007004:Hypoglycemic Agents; D007328:Insulin; D010982:Platelet-Derived Growth Factor; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat; D006854:Hydrocortisone