Contrary Effects of Lightly and Strongly Oxidized LDL With Potent Promotion of Growth Versus Apoptosis on Arterial Smooth Muscle Cells, Macrophages, and Fibroblasts

Abstract

The inhibition of experimental atherosclerosis by antioxidants and the presence of oxidized LDL (oxLDL) in atherosclerotic lesions indicate that oxLDL may play what is perhaps a primary role in atherogenesis. LDL promotes the growth of arterial smooth muscle cells (SMCs), and oxLDL has cytotoxic effects. Since excessive intimal growth alternating with necrosis is typical of atherosclerotic lesions, we wondered whether these extreme changes in the lesions could be related to the extreme effects of LDL and oxLDL on cells. We therefore examined the effects of increasing LDL oxidation on its capacity to induce cell growth or cell death and whether the latter could be due to apoptosis. Cells of the types present in the atherosclerotic artery used, ie, SMCs (human arterial), macrophages (human macrophage-like cell line THP-1), and human fibroblasts. Growth was evaluated by measuring the synthesis of DNA and culture size (MTT method) and apoptosis by using the in situ labeling of internucleosomally degraded DNA and, in the case of SMCs, the appearance of chromatin condensation. The oxidation of LDL was by UV or Fe ions. Shortly oxidized LDL had a markedly increased growth-promoting effect on all cell types. With prolonged exposure to UV, but not to Fe, LDL became increasingly cytotoxic, and this toxicity was paralleled by the appearance of apoptosis in all cell types. After prolonged UV treatment, low-molecular-weight material from the partially degraded LDL was responsible for the induction of apoptosis. The dual effect of oxLDL, ie, its strong growth-promoting effect or the induction of cell death by apoptosis, depending on the degree of change by oxidation, is compatible with the notion that oxLDL plays a role not only in atherogenesis but also more extensively in the development of the structure typical of the atherosclerotic lesion, with focal excessive growth alternating with necrosis.

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

“…It should be noted, however, that the aggregated LDL particles affected neither the binding activity to proteoglycan (contribute to extracellular accumulation) nor the uptake by the scavenger receptor (contribute to intracellular accumulation), suggesting that there should be no difference in biological functions between two particles (Lougheed and Steinbrecher, 1996). Bjorkerud and Bjorkerud (1996) have reported oxidationdependent dual effects of oxLDL on cell numbers, which is similar to our results. They showed that shortly UVoxidized LDL had a growth promoting effect while the strongly oxidized LDL became cytotoxic on several different cell types including macrophages.…”

“…Different investigators utilized different methods to oxidize LDL and present different criteria for LDL oxidation. For example, Bjorkerud and Bjorkerud (1996) and Auge, et al (1995) utilized UV-or Fe-mediated oxidation to prepare oxLDL while others used cell- (Quinn et al, 1985), enzyme- (Parhami et al, 1993) or copper- (Chai et al, 1996;Hardwick et al, 1996) mediated methods. They used different concentration and conditions of catalyst, and presented malondialdehyde (MDA) formation by thiobarbituric acid-reactive substances (TBARS) assay as a criterion for the oxidation extent.…”

The emergence of sedentary behaviour physiology and its effects on the cardiometabolic profile in young and older adults

“…Increasing concentration of LDL-C can cause an accumulation within the arterial intima (Björnheden et al 1996). These LDL-C particles become oxidised and bind to receptors on endothelial and smooth muscle cells causing apoptosis of smooth muscle cells (Björkerud and Björkerud 1996), impaired nitric oxide (NO) synthesis (Keaney et al 1996) and oxidative stress (Cominacini et al 2000). Macrophage secretion into the intimal space occurs to take up the oxidised LDL-C particles and consequently differentiate into foam cells (Rios et al 2013).…”

Role of macrophage and smooth muscle cell apoptosis in association with oxidized low-density lipoprotein in the atherosclerotic development

“…14,15 Oxidized low-density lipoprotein (oxLDL) is now considered to play a significant role not only in atherogenesis but also in the entire process of atherosclerosis such as the formation of foam cells and the fatty streak, and induction of smooth muscle cell migration and proliferation. [16][17][18] In addition, oxLDL is cytotoxic to cultured cells and induces both apoptosis and necrosis of cultured smooth muscle cells. 19 In 1994, Itabe et al 20 raised a monoclonal antibody directed against oxLDL (FOH1a/DLH3) to investigate whether oxLDL was synthesized in foam cells in vitro and in vivo.…”