title: Suppressor of cytokine signaling-3 and intimal hyperplasia in porcine coronary arteries following coronary intervention.
abstract: OBJECTIVE
  The growth and differentiation of cells is regulated by cytokines by binding to cell-surface receptors and activating intracellular signal transduction cascade. Suppressor of cytokine signaling (SOCS)-3 is a negative regulator of cytokines. In this study we examined the expression of SOCS-3 in porcine coronary artery smooth muscle cells (PCASMCs) in vitro and in proliferating smooth muscle cells of neointimal lesions after coronary artery intervention in a swine model.
  
  
  RESULTS
  PCASMCs were cultured and stimulated with TNF-α and/or IGF-1 individually or in combination. Protein expression of SOCS-3 was examined using Western blot. For in vivo studies, six female Yucatan miniswine were fed with special high cholesterol diet for 8 months. At 4 months of high cholesterol diet, animals underwent coronary balloon angioplasty. At the end of 8 months animals were euthanized, coronary arteries were isolated and morphological and histological studies were performed. Western blot data revealed significantly high SOCS-3 expression in PCASMCs in the presence of either TNF-α or IGF-1 (5-6 fold) alone. However, in the presence of both TNF-α and IGF-1 the SOCS-3 expression was significantly decreased (4-5 fold). Results from morphological studies including, H&E and Masson's trichrome stain showed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle α-actin and significantly increased proliferating cell nuclear antigen (PCNA) in neointimal lesion. Interestingly, there was significantly decreased expression of SOCS-3 in smooth muscle cells of neointima as compared to control.
  
  
  CONCLUSIONS
  These data suggest that SOCS-3 expression is decreased in proliferating smooth muscle cells of neointimal lesions. This leads to uncontrolled growth of vascular smooth muscle cells in injured arteries leading to restenosis. Therefore, local delivery of SOCS-3 gene at the site of injury after coronary artery intervention could regulate the proliferation of vascular smooth muscle cells and help in preventing the neointimal hyperplasia and restenosis.
authors.affiliation: Department of Biomedical Sciences and Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Gaurav K
authors.initials: GK
authors.lastname: Gupta
authors.forename: Kajari
authors.initials: K
authors.lastname: Dhar
authors.forename: Michael G
authors.initials: MG
authors.lastname: Del Core
authors.forename: William J
authors.initials: WJ
authors.lastname: Hunter
authors.forename: Georgios I
authors.initials: GI
authors.lastname: Hatzoudis
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D000199:Actins / Q000378:metabolism; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003331:Coronary Vessels / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006965:Hyperplasia; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology*
chemical_list: D000199:Actins; D002791:Cholesterol, Dietary; D018809:Proliferating Cell Nuclear Antigen; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I