Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice.
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.


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.
Zhou
Ji
J
Department of Pathology and Molecular Medicine, McMaster University, and the Henderson Research Centre, Hamilton, Ontario, Canada.
Lhoták
Sárka
S
Hilditch
Brooke A
BA
Austin
Richard C
RC
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000502:physiology; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology*; D015415:Biomarkers / Q000032:analysis; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D017510:Protein Folding; D013312:Stress, Physiological
D001057:Apolipoproteins E; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D002784:Cholesterol