Published Online
on April 4, 2005

A more recent version of this article appeared on April 12, 2005

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Submitted on July 12, 2004
Revised on November 9, 2004
Accepted on December 1, 2004

Activation of the Unfolded Protein Response Occurs at All Stages of Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice

Ji Zhou MD, PhD, árka Lhoták PhD, Brooke A. Hilditch BSc, and Richard C. Austin PhD^*

From the Department of Pathology and Molecular Medicine, McMaster University, and the Henderson Research Centre, Hamilton, Ontario, Canada.

^* To whom correspondence should be addressed. E-mail: raustin{at}thrombosis.hhscr.org.

Background--Apoptotic cell death contributes to atherosclerotic lesion instability, rupture, and thrombogenicity. Recent findings suggest that free cholesterol (FC) accumulation in macrophages induces endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and apoptotic cell death; however, it is not known at what stage of lesion development the UPR is induced in macrophages or whether a correlation exists between UPR activation, FC accumulation, and apoptotic cell death.

Methods and Results--Aortic root sections from apolipoprotein E-deficient (apoE^-/-) mice at 9 weeks of age (early-lesion group) or 23 weeks of age (advanced-lesion group) fed a standard chow diet were examined for markers of UPR activation (GRP78, phospho-PERK, CHOP, and TDAG51), apoptotic cell death (TUNEL and cleaved caspase-3), and lipid accumulation (filipin and oil red O). UPR markers were dramatically increased in very early intimal macrophages and in macrophage foam cells from fatty streaks and advanced atherosclerotic lesions. Although accumulation of FC was observed in early-lesion-resident macrophage foam cells, no evidence of apoptotic cell death was observed; however, UPR activation, FC accumulation, and apoptotic cell death were observed in a small percentage of advanced-lesion-resident macrophage foam cells.

Conclusions--UPR activation occurs at all stages of atherosclerotic lesion development. The additional finding that macrophage apoptosis did not correlate with UPR activation and FC accumulation in early-lesion-resident macrophages suggests that activation of other cellular mediators and/or pathways are required for apoptotic cell death.

Key words: immunohistochemistry • atherosclerosis • cholesterol • apoptosis

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