Lentiviral-mediated RNA interference of lipoprotein-associated phospholipase A2 ameliorates inflammation and atherosclerosis in apolipoprotein E-deficient mice

Abstract

Lipoprotein associated phospholipaseA2 (Lp-PLA2) overexpression is implicated in athero-sclerosis. In the present study, we evaluated the effects of lentiviral-mediated RNA interference (RNAi) of Lp-PLA2 on inflammation and atherosclerosis in apolipoproteinE-deficient mice. ApolipoproteinE-deficient mice were randomly allocated to control and experimental groups, and constrictive collars were used to induce plaque formation. Eight weeks after surgery, the lentiviral-mediated RNAi construct was used to silence expression of Lp-PLA2. Control and experimental lentivirus was transfected directly into carotid plaques or administered systemically. Tissues were collected for analysis 7weeks after transfection. Inflammatory gene expression in the plasma and atherosclerotic lesions was then determined at the mRNA and protein levels. We observed no differences in body weight and plasma lipid levels at the end of the investigation. However, the expression levels of Lp-PLA2 and pro-inflammatory cytokines were significantly reduced in the RNAi groups, compared to the controls, whereas the plasma concentration of anti-inflammatory cytokines was markedly increased. Moreover, our results demonstrated a significant reduction in plaque area and lipid content, as well as a rise in collagen content following RNAi treatment. Importantly, when comparing the two methods of viral delivery, we found that transluminal local transfection exhibited enhanced improvement of plaque stability as compared to systemic administration. Inhibition of Lp-PLA2 by lentiviral-mediated RNAi ameliorates inflammation and atherosclerosis in apolipoproteinE-deficient mice. In addition, transluminal local delivery of Lp-PLA2 shRNA is superior to systemic administration for stabilizing atherosclerotic plaques.