Regression of atherosclerosis plaques in apolipoprotein E-/- mice after lentivirus-mediated RNA interference of CD40

Background: A role of CD40 (cluster of differentiation 40) is suggested in development of atherosclerosis plaques, especially in advanced plaques. However, the role of lentiviruses carrying small interfering RNA (siRNA) of CD40 in progression and destabilization of advanced atherosclerotic plaques remains unknown. The aim of this study was to determine whether inhibition of CD40 signaling by lentivirus-mediated RNA interference (RNAi) could inhibit progression of atherosclerotic plaques and increase collagen production. Methods: Apolipoprotein E-deficient (ApoE(-/-)) mice aged 10 weeks were fed a high-fat diet and a constrictive collar was placed around right carotid arteries of these mice to induce plaques formation. The recombinant CD40-RNAi-Lentivirus (CD40-RNAi-LV) or negative control - green fluorescent protein - Lentivirus (NC-GFP-LV) were constructed and transfected into right carotid plaques respectively eight weeks after surgery. Results: CD40-RNAi-LV not only prevented plaques progression but also decreased plaques content of lipid, increased plaques content of collagen 6 weeks after lentivirus transfection. This effect reflected a marked decrease in the intima/media ratios (0.31 +/- 0.04 vs 0.68 +/- 0.05, P<0.05) and a diminished degree of lumen stenosis (intima/lumen ratios, 0.17 +/- 0.04 vs 0.33 +/- 0.40, P<0.05). Moreover, real-time polymerase chain reaction (RT-PCR) analysis of CD40-RNAi-LV group downregulated expressions of proinflammatory cytokines, chemokines and matrix metalloproteinases. Conclusions: Lentivirus-mediated CD40 silencing by siRNA treatment would be a new strategy to inhibit plaques progression and to reduce local inflammation through the antiinflammatory effects. (C) 2011 Elsevier Ireland Ltd. All rights reserved.