7b-Hydroxycholesterol induces Ca oscillations, MAP kinase activation and apoptosis in human aortic smooth muscle cells

نویسندگان

  • Mikko P.S. Ares
  • Isabella Pörn-Ares
  • Sara Moses
  • Johan Thyberg
  • Lisa Juntti-Berggren
  • Anna Hultgårdh-Nilsson
  • Bengt Kallin
  • Jan Nilsson
چکیده

In the present study, we characterize the early cytotoxic effects of 7b-hydroxycholesterol, a major cytotoxin in oxidized LDL, in human aortic smooth muscle cells. Within a few minutes after addition, 7b-hydroxycholesterol induced Ca oscillations with a frequency of :0.3–0.4 min. A few hours later, thapsigargin-sensitive Ca pools were depleted, indicating that 7b-hydroxycholesterol perturbs intracellular Ca homeostasis. The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 (but not JNK) were activated within 5 min after addition of 7b-hydroxycholesterol. The side-chain hydroxylated oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol were more potent in inducing apoptosis than 7b-hydroxycholesterol and cholesterol-5a,6aepoxide, as determined by TUNEL staining. Addition of TNFa (10 ng/ml) and IFNg (20 ng/ml) enhanced the cytotoxicity of oxysterols and potentiated apoptosis. The cytokines alone were not toxic to smooth muscle cells at these concentrations. 25-Hydroxycholesterol and 7b-hydroxycholesterol but not cholesterol inhibited protein synthesis at 4–8 h as determined by [S]methionine incorporation assay. Morphologically, oxysterol-induced cell death was characterized by disorganization of the ER and Golgi membranes. The Ca and ERK signals preceded the ultrastructural changes induced by 7b-hydroxycholesterol. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

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تاریخ انتشار 2000