HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

7-Ketocholesterol and cholesterol-5alpha,6alpha-epoxide induce smooth muscle cell migration and proliferation through the epidermal growth factor receptor/phosphoinositide 3-kinase/Akt signaling pathways.

Abstract
Oxysterols, the major components of oxidized low-density lipoproteins (ox-LDLs), are present in atherosclerotic plaque and are suggested to play an active role in plaque development. The formation of an atherosclerotic lesion occurs through activation of cellular events that include vascular smooth muscle cell (SMC) migration and proliferation. Therefore, we investigated the roles of two common oxysterols, 7-ketocholesterol (7-keto) and cholesterol-5alpha,6alpha-epoxide (alpha-epoxide) on SMCs. Our results showed that 7-keto and alpha-epoxide promoted SMC migration by a chemotactic assay, and induced mitogenic effects by MTT assay and BrdU assay. Specific inhibitors confirmed that MMPs, EGFR and PI3K are involved in oxysterol-induced SMC migration, while EGFR, ERK, Akt, and sphingomyelin/ceramide pathways might play a role in SMC proliferation. More, the co-immunoprecipitation study indicated that 7-keto and alpha-epoxide caused EGFR phosphorylation and there was an interaction between EGFR and PI3K. At protein expression level, Akt and ERK were activated, at messenger RNA level, MMP-2/9 mRNA was transcribed, at enzyme activity level, the MMP-2/9 enzyme activity were increased in SMCs treated with 7-keto and alpha-epoxide according to Western bolt, RT-PCR and a fluorogenic substrate. Taken together, we concluded that 7-keto and alpha-epoxide may be an atherogenic factor by stimulating SMC migration and proliferation.
AuthorsPo Lin Liao, Yu Wen Cheng, Ching Hao Li, Yan Ting Wang, Jaw Jou Kang
JournalToxicology letters (Toxicol Lett) Vol. 197 Issue 2 Pg. 88-96 (Aug 16 2010) ISSN: 1879-3169 [Electronic] Netherlands
PMID20466046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Ceramides
  • Intracellular Signaling Peptides and Proteins
  • Ketocholesterols
  • RNA, Messenger
  • Sphingomyelins
  • cholesterol alpha-oxide
  • Cholesterol
  • ErbB Receptors
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • 7-ketocholesterol
Topics
  • Animals
  • Aorta
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Ceramides (metabolism)
  • Cholesterol (analogs & derivatives, toxicity)
  • ErbB Receptors (metabolism)
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Intracellular Signaling Peptides and Proteins (metabolism)
  • Ketocholesterols (toxicity)
  • Matrix Metalloproteinase 2 (metabolism)
  • Matrix Metalloproteinase 9 (metabolism)
  • Muscle, Smooth, Vascular (cytology)
  • Myocytes, Smooth Muscle (cytology, drug effects)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphorylation
  • Protein Serine-Threonine Kinases (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • RNA, Messenger (genetics, metabolism)
  • Rats
  • Signal Transduction (drug effects)
  • Sphingomyelins (metabolism)
  • TOR Serine-Threonine Kinases

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: