Peroxisome Proliferator-Activated Receptor- γ 1 Gene Therapy Attenuates Atherosclerosis and Stabilizes Plaques in Apolipoprotein E-Deficient Mice

Abstract

Peroxisome proliferator-activated receptor-γ1 (PPARγ1) is an important transcription factor involved in atherosclerosis progression. Thus, PPARγ1 appears to be an interesting gene therapeutic target to favorably affect atherosclerosis development. The present study was carried out to test the hypothesis that PPARγ1 gene therapy may attenuate and stabilize atherosclerotic plaques in apolipoprotein E-knockout mice. The recombinant adenovirus carrying mouse PPARγ1 cDNA (AdPPARγ1) was constructed and AdPPARγ1 (5 × 10⁸ PFU) or AdGFP (5 × 10⁸ PFU), diluted to a total volume of 200 μl, was injected into the tail vein of mice (40 weeks of age and fed a high-fat diet) in two intervention groups (n = 20 each). Mice (n = 20) injected with phosphate-buffered saline (PBS) served as vehicle controls. The results showed that 4-week treatment with AdPPARγ1 attenuated atherosclerotic lesions, although the overall mRNA levels of CD36 were increased in the AdPPARγ1 group. Moreover, PPARγ1 gene overexpression stabilized atherosclerotic plaques as shown by the reduced depositions of lipids and macrophages and increased contents of smooth muscle cells and collagen within the plaques. In addition, marked upregulation of the mRNA levels of cholesterol efflux-related molecules such as liver X receptor α and ATP-binding cassette transporter A1 in liver, and downregulation of matrix metalloproteinase-9, human tissue factor, CD40, CD40 ligand, tumor necrosis factor-α, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, macrosialin, class A scavenger receptor, and macrophage migration inhibitory factor in aorta, were demonstrated in AdPPARγ1-treated animals. In contrast, there was no significant difference in aforementioned parameters between the AdGFP and PBS groups. In conclusion, overexpression of the PPARγ1 gene exerts beneficial effects in attenuating atherosclerosis progression and stabilizes vulnerable plaques. Thus, PPARγ1 might offer a promising gene therapeutic target against atherosclerosis.