Accumulation of LDL in rat arteries is associated with activation of tumornecrosis factor-alpha expression

Activation of vascular inflammation in response to hyperlipidemia is believ ed to play an important role during the early stages of atherogenesis. We d emonstrate here that exposure of cultured, rat aortic smooth muscle cells t o low density lipoprotein (LDL) stimulated tumor necrosis factor-alpha (TNF -alpha) mRNA and protein expression. Oxidative modification of LDL resulted in a reduction of this stimulatory effect. To analyze whether a similar re sponse also occurs in vivo, we used a recently developed model in which the effects of a rapid accumulation of human LDL in rat arteries can be studie d. As previously reported, epitopes specific for human apolipoprotein B beg an to accumulate in the aorta within 2 to 6 hours after injection of 6 mg o f human LDL. This was followed by expression of oxidized LDL-specific epito pes after 12 hours. There was no vascular expression of TNF-alpha at baseli ne or in phosphate-buffered saline-injected control rats. However, 24 hours after injection of native LDL, there was a marked induction of TNF-alpha m RNA and immunoreactivity in the aorta and other large arteries, whereas inj ection of oxidized LDL was without effect in this respect. Preincubation of LDL with the antioxidant probucol before injection markedly decreased the expression of TNF-alpha immunoreactivity. The present findings support the notion that LDL may activate arterial expression of TNF-alpha and suggest 1 possible mechanism for the inflammatory response in the early stages of at herosclerosis. The role of LDL oxidation in this process remains to be full y elucidated.