Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis

• DOI: 10.1073/pnas.1732494100
• Publication Date: 2003-09-02T17:27:00Z
• Authors: Bo Feng; Dajun Zhang; George Kuriakose; Cecillia M. Devlin; Mark Kockx; Ira Tabas
• Keywords: Niemann-Pick Diseases; 0301 basic medicine; Heterozygote; Mice, Inbred BALB C; Membrane Glycoproteins; Arteriosclerosis; Macrophages; Intracellular Signaling Peptides and Proteins; Apoptosis; Endoplasmic Reticulum; 3. Good health; Mice, Inbred C57BL; Mice; Necrosis; 03 medical and health sciences; Apolipoproteins E; Cholesterol; Niemann-Pick C1 Protein; In Situ Nick-End Labeling; Animals; Carrier Proteins; Engineering sciences. Technology

Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and likely promotes plaque instability, a precursor of acute vascular events. Macrophages in advanced lesions accumulate large amounts of unesterified cholesterol, which is a potent inducer of macrophage apoptosis. We have shown recently that induction of apoptosis in cultured macrophages requires cholesterol trafficking to the endoplasmic reticulum (ER). Moreover, macrophages from mice with a heterozygous mutation in the cholesterol-trafficking protein Npc1 have a selective defect in cholesterol trafficking to the ER and are protected from cholesterol-induced apoptosis. The goal of the present study was to test the importance of intracellular cholesterol trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in Npc1 +/+ ; Apoe -/- and Npc1 +/- ; Apoe -/- mice. Although advanced lesions in Npc1 +/+ ; Apoe -/- mice had extensive acellular areas that were rich in unesterified cholesterol and macrophage debris, the lesions of Npc1 +/- ; Apoe -/- mice were substantially more cellular and less necrotic. Moreover, compared with Npc1 +/- ; Apoe -/- lesions, Npc1 +/+ ; Apoe -/- lesions had a greater number of large, TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling)-positive areas surrounding necrotic areas, indicative of macrophage apoptosis. These differences were observed despite similar total lesion area and similar plasma lipid levels in the two groups of mice. These data provide in vivo evidence that intact intracellular cholesterol trafficking is important for macrophage apoptosis in advanced atherosclerotic lesions and that the ER-based model of cholesterol-induced cytotoxicity is physiologically relevant. Moreover, by showing that lesional necrosis can be diminished by a subtle defect in intracellular trafficking, these findings suggest therapeutic strategies to stabilize atherosclerotic plaques.