GENETIC-EVIDENCE FOR A COMMON PATHWAY MEDIATING OXIDATIVE STRESS, INFLAMMATORY GENE INDUCTION, AND AORTIC FATTY STREAK FORMATION IN MICE

In a previous survey of inbred mouse strains on an atherogenic diet; w e observed that the susceptibility to aortic atherosclerotic lesion fo rmation was associated with the accumulation of lipid peroxidation pro ducts, induction of inflammatory genes, and the activation of NF-kB-li ke transcription factors (Liao, F., A. Andalibi, F. C. deBeer, A. M. F ogelman, and A. J. Lusis. 1993. J. Clin. Invest. 91:2572-2579). We hyp othesized that the inflammation-related processes were stimulated by o xidized lipids, since injection of minimally oxidized LDL (MM-LDL) act ivated the same set of genes. We now report that the induction of infl ammatory genes and activation of NF-kB-like transcription factors cose gregate with aortic atherosclerotic lesion formation in BXH recombinan t inbred strains derived from parental C57BL/6J (susceptible) and C3H/ HeJ (resistant) mice. In addition, the accumulation of hepatic conjuga ted dienes exhibited a significant correlation with inflammatory gene activation. These results provide strong evidence for the role of infl ammatory mediators inducible by oxidative stress in atherogenesis. The y also suggest that a major gene contributing to aortic lesion develop ment in this mouse model, designated Ath-1, may control either the acc umulation of lipid peroxides in tissues or the cellular responses to s uch lipid peroxides.