Decorin overexpression reduces atherosclerosis development in apolipoprotein E-deficient mice.
Atherosclerosis results from accumulation of macrophages and extracellular matrix in the arterial wall. Decorin, a small matrix proteoglycan, is able to regulate cell proliferation, migration and growth factors' activity. We investigated the effect of decorin overexpression on atherosclerosis progression in apolipoprotein E-deficient (ApoE(-/-)) mice. Female ApoE(-/-) mice, 10 weeks old (early treatment, n = 20) and 20 weeks old (delayed treatment, n = 20) were administered intravenously with either an adenovirus (2.5 x 10(9) plaque-forming units/mouse) containing human decorin gene (Ad-Dcn) or beta-galactosidase (LacZ), or PBS. Transgenic decorin was mainly expressed in the liver, and was secreted in the plasma up to 4 weeks. Six weeks after treatment, no significant difference in aortic root lesion size was observed between LacZ- and PBS-control groups. In contrast, Ad-Dcn-treated mice showed significantly reduced atherosclerotic lesions as compared to controls in both early and delayed treatment groups (2.9 +/- 1.1% versus 5.5 +/- 0.4%; p = 0.004 and 13.4 +/- 1.3% versus 19.9 +/- 1.41%; p = 0.009, respectively). In parallel, macrophage, gelatinase activity and collagen plaque content were also reduced. Interestingly, plasma triglycerides were reduced and decorin formed complexes with transforming growth factor-beta1 (TGF-beta1) that resulted in reduced circulating free-TGF-beta1. In conclusion, systemic overexpression of decorin reduces inflammation, triglycerides and fibrosis in atherosclerotic plaques of ApoE(-/-) mice resulting in slowing down of disease progression.
Al Haj Zen
Ayman
A
Inserm EMI-0016, Rene Descartes Medical School (Necker), University Paris 5, 156, rue de Vaugirard, 75015 Paris, France. aymanzen@aol.com
Caligiuri
Giuseppina
G
Sainz
Julie
J
Lemitre
Mathilde
M
Demerens
Corinne
C
Lafont
Antoine
A
D000682:Amyloid / Q000097:blood; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism*; D049109:Cell Proliferation; D058575:Decorin; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000096:biosynthesis* / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D000682:Amyloid; D001057:Apolipoproteins E; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D011994:Recombinant Proteins; D014280:Triglycerides; D012313:RNA