Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Abstract

Low density lipoprotein (LDL) oxidation is believed to play an important role in the development of atherosclerotic plaques [1][2][3][4][5]. This view is supported by LDL with characteristics similar to those of oxidatively modified LDL being present in atheromatous lesions [6]. Studies in cultured cells have demonstrated that oxidized LDL is chemotactic for monocytes and stimulates monocyte endothelial cell interaction [7,8]. It can also cause initial endothelial cell damage and increase uptake by scavenger receptors on macrophages, leading to cholesterol accumulation and foam cell formation [7,9].Oxidative modification of LDL is not likely to occur in circulation [3]. In view of the difficulties in identifying oxidized lipoprotein in plasma, many workers have attempted to analyse the oxidation susceptibility of isolated LDL particles in vitro [10,11]. If LDL can penetrate macrophages only after its modification [3], the ability of LDL to resist oxidation could be an Diabetologia (1997) Summary Troglitazone is a new oral antidiabetic agent able to reduce lipid peroxidation. In this study we evaluated its effect on the susceptibility of LDL and HDL to in vitro oxidation induced by copper ions and endothelial cells. In Cu ++ -induced LDL modification, different amounts of troglitazone were added to aliquots of the same pool of plasma with subsequent ultracentrifuge separation of LDL and HDL. Differences in LDL and HDL susceptibility to in vitro oxidation with Cu ++ were studied by measuring the changes in fluorescence intensity (expressed as lag phase). LDL derived from plasma incubated with different amounts of troglitazone were also incubated with umbilical vein endothelial cells (HU-VEC), the modification being monitored by LDL relative electrophoretic mobility and fluorescence. During Cu ++ -and HUVEC-induced LDL oxidation, the decay rate of vitamin E, and the potency of troglitazone as a radical scavenger in comparison with vitamin E were also studied. Troglitazone determined a significant, dose-dependent decrease in Cu ++ -induced LDL and HDL oxidation. Incubation with HUVEC was also followed by a progressive, significant decrease of LDL relative electrophoretic mobility and fluorescence intensity. During Cu ++ -and HU-VEC-induced-LDL modification, troglitazone significantly reduced the rate of vitamin E decay. In this study we also demonstrated that under the same oxidative stress, troglitazone was much more potent as a radical scavenger than vitamin E. In conclusion, the results demonstrate that troglitazone can reduce LDL and HDL in vitro oxidation and that, during this process, it can protect vitamin E. In addition to ensuring blood glucose control, the drug may therefore be useful in inhibiting lipoprotein peroxidation. [Diabetologia (1997)

Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes

“…The thiazolidinedione insulin sensitizer troglitazone is composed of a vitamin E moiety conjugated to a dione moiety. The antioxidative capacity of this compound has been reported [27,28] and may have a role in its insulin sensitizing action. Vitamin C is a clinically used antioxidant that is water soluble and has potential effects on peripheral glucose utilization [6,29].…”

Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion

“…Generation of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate from phospholipids as well as ceramide derived from sphingomyelin triggers the progression of cell cycles. In response to a decrease in intracellular lipids from lipase suppression, lipoprotein receptor expression may be upregulated, whereas NF-kB may be stimulated to increase the expression of lipoprotein receptors (47,48). Also, a lack of lipids may alter cell proliferation and trigger apoptosis.…”

Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats.

“…This possibility is supported by the following evidence. First, the concentrations of troglitazone that we used in vitro (3 µmol/l) were much smaller than those of ␣-tocopherol (50 µmol/l), which was used as an antioxidant in the previous studies (61). Second, the activation of DAG kinase by troglitazone was observed only in glomeruli of diabetic rats or in mesangial cells cultured under high glucose conditions, whereas ␣-tocopherol was shown to activate DAG kinase in glomeruli of both control and diabetic rats (14).…”