Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle cells

Lysyl oxidase is an essential catalyst for the cross-linking of extracellul ar collagen and elastin. Abnormalities in lysyl oxidase activity may contri bute to the pathogenesis of arterial diseases characterized by abnormal mat rix remodeling. This study tested the hypothesis that interferon (IFN)-gamm a, a proinflammatory cytokine present in aortic aneurysm and arteriosclerot ic plaque rupture, downregulates lysyl oxidase gene expression in rat aorti c smooth muscle cells. Steady-state lysyl oxidase mRNA levels decreased in a concentration- and time-dependent manner to 30% of control levels after 2 4 hours of treatment with IFN-gamma. Cell layer lysyl oxidase activity decr eased in parallel vclith the observed changes in steady-state mRNA. Nuclear runoff studies suggested that transcriptional regulation was responsible f or at least 40% of the observed downregulation. mRNA decay studies suggeste d that IFN-gamma also deereased lysyl oxidase mRNA half-life from 9 to 6 ho urs. Downregulation of lysyl oxidase by IFN-gamma did not appear to require new protein synthesis. This study documents that IFN-gamma downregulates l ysyl oxidase gene expression in rat aortic smooth muscle cells by transcrip tional and posttranscriptional mechanisms. if similar regulation occurs in vivo, it is possible that IFN-gamma-mediated changes in lysyl oxidase may c ontribute to arterial diseases characterized by abnormal extracellular matr ix.