title: G-protein-coupled receptor kinase interacting protein-1 mediates intima formation by regulating vascular smooth muscle proliferation, apoptosis, and migration.
abstract: OBJECTIVE
  The G-protein-coupled receptor kinase interacting protein-1 (GIT1) is a scaffold protein that is important for phospholipase Cγ and extracellular signal-regulated kinase 1/2 signaling induced by angiotensin II and epidermal growth factor. Because GIT1 regulates signaling by several vascular smooth muscle cell (VSMC) growth factors, we hypothesized that intima formation would be inhibited by GIT1 depletion.
  
  
  RESULTS
  Complete carotid ligation was performed on GIT1 wild-type and knockout (KO) mice. We compared changes between GIT1 wild-type and KO mice in carotid vascular remodeling, VSMC proliferation, and apoptosis in vivo and in vitro. Our data demonstrated that GIT1 deficiency significantly decreased intima formation after carotid ligation as a result of both reduced VSMC proliferation and enhanced apoptosis. To confirm the effects of GIT1 in vitro, we performed proliferation and apoptosis assays in VSMC. In mouse aortic smooth muscle cells (MASM), we found that the growth rate and [3H]-thymidine incorporation of the GIT1 KO MASM were significantly decreased compared with the wild-type MASM. Cyclin D1, which is a key cell cycle regulator, was significantly decreased in GIT1 KO cells. Serum deprivation of GIT1 KO MASM increased apoptosis 3-fold compared with wild-type MASM. Treatment of rat aortic smooth muscle cells with GIT1 small interfering RNA impaired cell migration. Both phospholipase Cγ and extracellular signal-regulated kinase 1/2 signaling were required for GIT1-dependent VSMC proliferation and migration, whereas only phospholipase Cγ was involved in GIT1-mediated VSMC apoptosis.
  
  
  CONCLUSIONS
  GIT1 is a novel mediator of vascular remodeling by regulating VSMC proliferation, migration, and apoptosis through phospholipase Cγ and extracellular signal-regulated kinase 1/2 signaling pathways.
authors: Aab Cardiovascular Research Institute, University of Rochester, Box CVRI, 601 Elmwood Ave, Rochester, NY 14642, USA. Jinjiang_pang@URMC.rochester.edu
authors: Jinjiang
authors: J
authors: Pang
authors: Xiangbin
authors: X
authors: Xu
authors: Xiaoqun
authors: X
authors: Wang
authors: Syamantak
authors: S
authors: Majumder
authors: Jing
authors: J
authors: Wang
authors: Vyacheslav A
authors: VA
authors: Korshunov
authors: Bradford C
authors: BC
authors: Berk
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases