Tumor necrosis factor-a in atherosclerosis

Tumor necrosis factor-a in atherogenesis Stefan Jovinge, Department of Medicine, King Gustaf Vth Research, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden The presence of inflammatory cells is prominent at all phases of the atherosclerotic process leaving no doubt that the inflammation is of central importance in atherosclerosis. The recruitment of inflammatory cells into the vessel wall is therefore a key event in early lesion formation. Hypercholesterolemia, which is one of the most important risk factors for cardiovascular disease, has been shown to lead to an accumulation of lipids in the vessel wall where local oxidative processes modify them. Oxidized LDL particles have cytotoxic as well as pro-inflammatory properties. Tumor necrosis factor (TNF)-a is a cytokine central to the inflammatory reaction. Moreover, TNFa plays an important role in the induction of matrix degrading enzymes necessary for the SMC migration seen in the further development of the atherosclerotic lesion. TNFa has also a well-established role in the role in triglyceride metabolism in the sense that it inhibits the major enzyme involved in degradation of triglycerides, lipoprotein lipase, leading to increased levels of triglycerides in the circulation of animals with high levels of TNFa. In addition TNFa has been found to influence glucose metabolism by inhibiting glucose transport proteins as well as insulin receptor signaling. Moreover, insulin resistance has been shown to be associated an increased expression of TNFa in adipose as well as muscle tissue. The major objectives of this investigation were to study the effect of oxidized LDL on the expression of cytokines and their role in the atherosclerotic process. Oxidized LDL was shown to increase secretion of smooth muscle cell SMC mitogens from monocyte/macrophages. TNFa was established to be the major mitogen released by these cells. The effect of oxidized LDL on monocyte/macrophages was mediated by activation of the transcription factor AP-I. TNFa did induce a transient depolymerization of stress fibers in vascular smooth muscle cells which corresponded to an increased cytokinesis of these cells into cell culture wounds. The expression of the transcription factor ets-l gene was also increased these cells. Oxidized LDL was also shown to induce primary necrotic cell death of vascular SMC. The cytokines TNFa and y-interferon had no obvious impact on cell survival, but in combination with oxidized LDL they induced a significant increase in the frequency of cells undergoing cell death by apoptosis. Following injection of LDL, Sprague-Dawley rats accumulated LDL in the vasculature that became oxidatively modified. LDL oxidized prior to injection accumulated in the liver and not in the vasculature. The accumulation of oxidized LDL in the arteries following LDL injection coincided with induction of TNFa protein expression in the vessel wall. This expression was almost completely abolished in rats injected with LDL pre-incubated with the anti-oxidant probucol. Young post-myocardial infarction patients were found to have higher plasma levels of TNFa than age matched controls. Among hyperlipidemic patients TNFa correlated with VLDL triglycerides and cholesterol while there was an inverse relation to HDL cholesterol. In patients treated with bezafibrate VLDL triglycerides levels were reduced by 35% without any significant change in TNFa levels. Moreover, TNFa levels were found to correlate with fasting glucose and proinsulin levels. In conclusion our results show that oxidized LDL has a pro-inflammatory effect by inducing expression of TNFa. They also show that TNFa stimulates migration of vascular cells and that oxidized LDL in combination with the cytokines TNFa and y-interferon induces apoptosis. Finally, they suggest that TNFa has a role in the disturbances of triglyceride and glucose metabolism frequently observed in young patients with myocardial infarction. Key words: atherosclerosis, oxidized low-density lipoprotein, monocytes, tumor necrosis factor-a, cytokinesis, ets-l, matrix metalloproteinases, apoptosis, glucose metabolism, insulin resistance, myocardial infarction ISBN 91-628-2486-