Effects of Chimeric Decoy Oligodeoxynucleotide in the Regulation of Transcription Factors NF‐κB and Sp1 in an Animal Model of Atherosclerosis

Abstract

Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Modulation of NF-κB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF-κB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF-κB and Sp1-binding sites to suppress these transcription factors simultaneously and to test chimeric decoy for anti-atherogenic effects in an atherogenic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODNs were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet-induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication.