title: Insulin-like growth factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells.
abstract: A balance between programmed cell death and survival of vascular smooth muscle cells (VSMC) in the fibrous cap, which is primarily composed of VSMC and extracellular matrix, appears to best correlate with plaque instability or stability and is controlled by growth factors and cytokines. Autophagy is also involved in programmed cell death. We assessed the effect of TNF-alpha and insulin-like growth factor-1 (IGF-1) on the expression of autophagic genes, microtubule-associated protein 1 light chain 3 (MAPLC-3) and Beclin-1 in VSMC isolated from atherosclerotic plaques. Transmission electron microscopy showed a significantly higher number of vacuolated cells in the TNF-alpha-treated VSMC and a markedly lower number in the IGF-1-treated VSMC when compared with the untreated control group. TNF-alpha-induced MAPLC-3 mRNA expression through c-jun N-terminal kinase and protein kinase B pathways and induced Beclin-1 protein expression through the c-jun N-terminal kinase pathway. Expression of MAPLC-3 and Beclin-1 correlated with autophagic cell death of plaque VSMC. IGF-1 inhibited MAPLC-3 mRNA transcripts through the Akt pathway. These findings suggest that the expression of autophagy genes can be influenced by IGF-1 and TNF-alpha through c-jun N-terminal kinase or Akt pathways and autophagy might be involved in the regulation of plaque stability.
authors.affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Deepak M
authors.initials: DM
authors.lastname: Gangahar
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy; D000071186:Beclin-1; D015153:Blotting, Western; D016893:Carotid Stenosis / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D002469:Cell Separation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases