Peroxisome proliferator-activated receptor-gamma1 gene therapy attenuates atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice.
Peroxisome proliferator-activated receptor-gamma1 (PPARgamma1) is an important transcription factor involved in atherosclerosis progression. Thus, PPARgamma1 appears to be an interesting gene therapeutic target to favorably affect atherosclerosis development. The present study was carried out to test the hypothesis that PPARgamma1 gene therapy may attenuate and stabilize atherosclerotic plaques in apolipoprotein E-knockout mice. The recombinant adenovirus carrying mouse PPARgamma1 cDNA (AdPPARgamma1) was constructed and AdPPARgamma1 (5 x 10(8) PFU) or AdGFP (5 x 10(8) PFU), diluted to a total volume of 200 mul, 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 AdPPARgamma1 attenuated atherosclerotic lesions, although the overall mRNA levels of CD36 were increased in the AdPPARgamma1 group. Moreover, PPARgamma1 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 alpha and ATP-binding cassette transporter A1 in liver, and downregulation of matrix metalloproteinase-9, human tissue factor, CD40, CD40 ligand, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, macrosialin, class A scavenger receptor, and macrophage migration inhibitory factor in aorta, were demonstrated in AdPPARgamma1-treated animals. In contrast, there was no significant difference in aforementioned parameters between the AdGFP and PBS groups. In conclusion, overexpression of the PPARgamma1 gene exerts beneficial effects in attenuating atherosclerosis progression and stabilizes vulnerable plaques. Thus, PPARgamma1 might offer a promising gene therapeutic target against atherosclerosis.
Hu
Qin
Q
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, China.
Zhang
Xian Jun
XJ
Zhang
Cheng
C
Zhao
Yu Xia
YX
He
Hong
H
Liu
Chun Xi
CX
Feng
Jin Bo
JB
Jiang
Hong
H
Yang
Fa Lin
FL
Zhang
Chun Xiang
CX
Zhang
Yun
Y
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D008055:Lipids / Q000032:analysis* / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism
D001057:Apolipoproteins E; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; D047495:PPAR gamma; D020782:Matrix Metalloproteinases