Regression of atherosclerosis in apolipoprotein E-deficient mice by lentivirus-mediated gene silencing of lipoprotein-associated phospholipase A₂
2012
Zhang, Hui | Zhang, Jinying | Shen, Deliang | Zhang, Li | He, Fei | Dang, Yuhua | Li, Ling
Overexpression of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is implicated in atherosclerosis. We tested the hypothesis that lentivirus-mediated Lp-PLA₂ silencing could inhibit atherosclerosis in apolipoprotein E-deficient mice. Sixty eight apolipoprotein E-deficient mice were fed a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC) and RNA interference (RNAi) groups. Lp-PLA₂ RNAi or scrambled NC lentivirus viral suspensions were constructed and transfected into the carotid plaques 8weeks after surgery; the control group was administered saline. The carotid plaques were assessed 7weeks later using hematoxylin and eosin, Masson’s trichrome and oil red O staining; plasma and lesion inflammatory gene expression were examined using ELISAs and real-time PCR. Seven weeks after transfection, the serum concentration and plaque mRNA expression of Lp-PLA₂ was significantly lower in the RNAi group, and lead to reduced local and systemic inflammatory gene expression. Lp-PLA₂ RNAi also ameliorated plaque progression, reduced the plaque lipid content and increased the plaque collagen content. The effects of Lp-PLA₂ RNAi were independent of serum lipoprotein levels, as the triglyceride and total cholesterol levels of the control, NC and RNAi groups were not significantly different. These findings support the hypothesis that lentivirus-mediated Lp-PLA₂ gene silencing has therapeutic potential to inhibit atherosclerosis and increase plaque stability, without altering the plasma lipoprotein profile.
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