Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages

Abstract

Objective-Lipid-loaded macrophage-derived foam cells populate atherosclerotic lesions and produce many pro-inflammatory and plaque-destabilizing factors. An excessive accumulation of extensively oxidized low-density lipoprotein (OxLDL) or free cholesterol (FC), both of which are believed to be major lipid components of macrophages in advanced lesions, rapidly induces apoptosis in macrophages. Indeed, there is evidence of macrophage death in lesions, but how the surviving macrophages avoid death induced by OxLDL, FC, and other factors is not known. Methods and Results-Minimally oxidized LDL (mmLDL), which is an early product of progressive LDL oxidation in atherosclerotic lesions, countered OxLDL-induced or FC-induced apoptosis and stimulated macrophage survival both in cell culture and in vivo. DNA fragmentation and caspase-3 activity in OxLDL-treated peritoneal macrophages were significantly reduced by coincubation with mmLDL. In a separate set of experiments, mmLDL significantly reduced annexin V binding to macrophages in which apoptosis was induced by FC loading. In both cellular models, mmLDL activated a pro-survival PI3K/Akt signaling pathway, and PI3K inhibitors, wortmannin and LY294002, eliminated the pro-survival effect of mmLDL. Immunohistochemical examination demonstrated phospho-Akt in murine atherosclerotic lesions. Conclusions-Minimally

Oxidized LDL attenuates apoptosis in monocytic cells by activating ERK signaling

“…Although high concentrations of OxLDL are cytotoxic for cells of the vascular wall, cytoprotective actions of OxLDL have been reported at lower doses in phagocytes (7,8). Recent studies suggest that cytoprotection by OxLDL depends on the degree of its oxidative modification as well as OxLDL inclusion in immune complexes (9,10).…”

Attenuated suppression of the oxidative burst by cells dying in the presence of oxidized low density lipoprotein

“…In mouse peritoneal macrophages, oxLDL initiates an apoptotic program ( 18,27,28 ), while human macrophages die by necrosis ( 29 ). Moreover, pro-survival effects of oxLDL were also observed, with the notion that the degree of LDL oxidation appears important in balancing pro-versus antiapoptotic responses ( 19,28 ).…”

Diabetes mellitus and apoptosis: inflammatory cells

“…Both of these factors can induce apoptosis in cultured macrophages and there is evidence to support this effect in plaque development. However, the form in which this lipid occurs has also been shown to be important, with minimally oxidised LDL, common in early lesions, countering ox-LDL-induced and FC-induced apotosis via Akt-dependent process both in culture and in vivo [140]. Indicating that at an early stage this process may contribute to foam cell proliferation and lesion development.…”