Chronic exposure of smooth muscle cells to minimally oxidized LDL results in depressed inositol 1,4,5-trisphosphate receptor density and Ca2+ transients

Hamid Massaeli, J. Alejandro Austria, Grant N. Pierce

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Abstract

Oxidized LDL (oxLDL) (0.1 mg/mL) increased [Ca2+](i) in vascular smooth muscle cells (VSMCs) within 5 to 10 seconds of incubation. This increase was mediated via an inositol 1,4,5-trisphosphate (IP3)-dependent release of Ca2+ from the sarcoplasmic reticulum. However, atherosclerosis is a gradual process in which VSMCs are more likely exposed to low concentrations of oxLDL over extended periods rather than acute exposures. It is very possible, therefore, that lower [oxLDL] and longer exposure times may induce a very different response with regard to regulation of [Ca2+](i). VSMCs were incubated with 4- to 100-fold lower [oxLDL] for up to 6 days. The conditions were not cytotoxic. Basal [Ca2+](i) was not altered. Surprisingly, however, after chronic exposure to oxLDL, a brief addition of oxLDL (0.1 mg/mL) or norepinephrine failed to elicit the expected rise in Ca2+(i). Because the acute effects of oxLDL on control cells were mediated through an IP3-dependent pathway, we investigated the integrity of the VSMC IP3 receptors. Immunocytochemical analysis and Western blots revealed a depression in the density of IP3 receptors after chronic exposure of VSMCs to oxLDL. These changes in IP3 receptors have significance under atherosclerotic conditions as well. Immunocytochemical analysis revealed a decrease in IP3 receptor density in the medial layer under atherosclerotic plaques in situ. Our data, therefore, demonstrate a striking difference between the acute and chronic effects of oxLDL on VSMC calcium. Whereas acute exposure to oxLDL stimulates [Ca2+](i), chronic exposure results in depressed Ca2+ transients, apparently through a decrease in IP3 receptor density. These changes have functional implications for the atherosclerotic vessel in vivo, and our data implicates oxLDL in this process.

Original languageEnglish
Pages (from-to)515-523
Number of pages9
JournalCirculation Research
Volume85
Issue number6
DOIs
Publication statusPublished - 17 Sep 1999

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Keywords

  • Atherosclerosis
  • Ca
  • Oxidized LDL
  • Sarcoplasmic reticulum
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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