MOLECULAR MECHANISMS OF CONTROL OF AORTIC FIBROSIS

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The excess deposition of extracellular fibers of collagen and elastin in fibrotic arterial disease is a major source of the mass of occlusive vascular lesions. Lysyl oxidase, the enzyme which catalyzes the oxidation of lysine and cross linking of collagen and elastin, plays a critical, controlling role in this process and thus is a vulnerable target for intervention in fibrotic arterial disease. Nevertheless, very little information presently exists about regulation of this catalyst at the transcriptional or post-transcriptional levels. However, our preliminary data now reveal that the expression of this enzyme is strongly up- regulated in vascular smooth muscle cells at the post-transcriptional level as proliferation is inhibited by transforming growth factor-beta1, evidenced by a marked reduction in rates of mRNA decay. In addition, analyses of lysyl oxidase promoter constructs in aortic smooth muscle cells reveal that promoter activity is prominently affected by serum- dependent changes in cell proliferation and co-transfection with B-myb. The molecular bases of this important regulatory effects will be analyzed in this project, determining the cis-elements in LO mRNA in the LO promoter mediating these effects, and characterizing the protein trans- acting factors that specifically interact with them under each perturbed condition. In addition, we have evidence by microscopic, immunochemical and enzymatic approaches that lysyl oxidase is prominently localized and appears to function within the nucleus of the arterial smooth muscle cell. The significance of this finding will be pursued, determining the nuclear protein substrates and products generated within them by the enzyme, and assessing for the functional consequences of this localization on proliferation and gene expression by the arterial smooth muscle cell. These studies will be carried out in close collaboration with other projects within this program as a natural consequence of their interests in collagen and elastin and in B-myb and adenosine ligands which we have noted perturb the expression of this enzyme.