Foam Cell Apoptosis and the Development of the Lipid Core of Human Atherosclerosis

Abstract

A characteristic feature of the advanced atherosclerotic lesion is the acellular lipid core, which appears to result at least partly from the death of macrophage foam cells. This study shows that foam cell death at the edge of the lipid core includes both necrosis and apoptosis and that remnants of apoptotic nuclei are present within the lipid core. Apoptotic cells were identified by transmission electron microscopy and by nick end‐labelling using terminal deoxynucleotidyl transferase (TUNEL). Some TUNEL‐positive cells also expressed proliferating cell nuclear antigen (PCNA). The cause of foam cell death in atherogenesis is unknown, but oxidized low‐density lipoprotein (LDL) can cause macrophage apoptosis in vitro and might therefore play a role in the formation and enlargement of the lipid core.

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

“…Oxidized-LDL bound to HNE-adducted apoB has a lower affinity for the apoB/E receptors that are expressed in most cell lines, except macrophages. Such modified LDLs are then reoriented toward scavenger receptors, expressed at the surface of macrophages and smooth muscle cells, leading to the Low levels of HNE in tumor tissues compared with healthy tissues, rTGFb1 [46][47][48]49 High levels of HNE in cancer tissues [50][51][52][53][54][55] Luminal HNE triggers the positive selection of preneoplastic cells in colorectal cancer 14,59 Atherosclerosis 37 The subsequent atheromatous plaque formation involves macrophage infiltration and activation of smooth muscle cells leading to fibrogenesis. HNE can particularly form adducts with PDGFR (platelet-derived growth factor receptor) in atherosclerotic aortas and the use of the antioxidant hydralazine prevents HNE-related adduction and slows the progression of the disease.…”

Apoptosis in the vasculature: mechanisms and functional importance

“…Several studies have shown evidence for in situ apoptotic cell death in animal and human atherosclerotic plaques (BjoÈ rkerud & BjoÈ rkerud, 1996;Cai et al, 1997;Geng & Libby, 1995;Han et al, 1995;Hegyi et al, 1996;Isner et al, 1995;Kockx et al, 1996;Mallat et al, 1997). Apoptosis, which is almost absent in normal arteries, becomes barely detectable in fatty streaks and is more abundant in advanced plaques.…”

“…Apoptosis, which is almost absent in normal arteries, becomes barely detectable in fatty streaks and is more abundant in advanced plaques. All cell types are involved, including SMCs, macrophages, T-lymphocytes (BjoÈ rkerud & BjoÈ rkerud, 1996;Cai et al, 1997;Geng & Libby, 1995;Han et al, 1995;Hegyi et al, 1996;Isner et al, 1995;Kockx et al, 1996;Mallat et al, 1997) and luminal endothelial cells (Tricot et al, 2000). Removal of apoptotic cells in human plaques may be ine cient, as a signi®cant percentage of secondary necrosis is observed.…”

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…2,8 Apoptotic cell death is a hallmark feature of both animal and human atherosclerotic lesions. [9][10][11] Apoptotic cells can be observed throughout advanced atherosclerotic lesions, but are most prominent in and around the lipid-rich core. It has been suggested that apoptosis increases the risk of lesion rupture by decreasing the number of viable smooth muscle cells necessary for collagen production and stabilization of the fibrous cap.…”