Abstract 710: A Novel Mechanism by Which CPI-17 Is Down-regulated in Cultured Vascular Smooth Muscle Cells and Tissues by TNFα and in C57BL/6 Mice by Lipopolysaccharide

Objectives: Sepsis is characterized by a severe inflammatory response to infection, and its complications, including hypotension, can be fatal. It has long believed that hypotension in sepsis occur as a result of failure of the vascular smooth muscle cells (VSMC) to constrict. However, the molecular mechanism that links inflammation and decreases in vasoconstriction is largely unknown. Approaches and Results: CPI-17, a key regulator in vasoconstriction, was markedly decreased in mesentery arteries (MA) in mice injected with lipopolysaccharide (LPS). Incubation of cultured MA or VSMC with TNFα had similar effects on CPI-17 as LPS injection in mice. To identify transcriptional factors that respond to TNFα to suppress CPI-17 expression, we cloned a 1 kb murine CPI-17 promoter (-1,015 to +2 bp). Promoter deletion analysis revealed that a CPI-17 promoter region (-115 to -50 bp) was critical for TNFα to inhibit CPI-17 promoter activity. Bioinformatics analysis revealed this region contained 3 GC boxes that are ...