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(Circulation Research. 1999;85:515-523.)
© 1999 American Heart Association, Inc.

Cellular Biology

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

From the Division of Stroke and Vascular Disease, St. Boniface General Hospital Research Centre, and Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.

Correspondence to Grant N. Pierce, PhD, FACC, Director, Division of Stroke and Vascular Disease, St. Boniface General Hospital Research Centre, 351 Tache Ave, Winnipeg, Manitoba, Canada R2H 2A6. E-mail pierce{at}sbrc.umanitoba.ca

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.

Key Words: oxidized LDL • vascular smooth muscle cell • atherosclerosis • Ca²⁺ • sarcoplasmic reticulum

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