Overexpression of TGF-ß1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice

• Published in: PloS one Vol. 7; no. 7; p. e40990
• Main Authors: Reifenberg, Kurt, Cheng, Fei, Orning, Carolin, Crain, Jeanine, Küpper, Ines, Wiese, Elena, Protschka, Martina, Blessing, Manfred, Lackner, Karl J, Torzewski, Michael
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-07-2012; Public Library of Science (PLoS)
• Subjects: Animals; Aorta; Aortic arch; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis; Atherogenesis; Atherosclerosis; B cells; Biology; Collagen; Cytokines; Female; Gene expression; Genetic engineering; Growth factors; Immunohistochemistry; Inflammatory diseases; Kinases; Laboratory animals; Lesions; Macrophages; Macrophages - metabolism; Medical research; Medicine; Mice; Mice, Knockout; Mice, Transgenic; Muscles; Mutants; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - metabolism; Plaques; Receptors; Rodents; Signal transduction; Smooth muscle; Transcription factors; Transforming growth factor; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factors; Transgenic animals; Transgenic mice; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040990

Although macrophages represent the hallmark of both human and murine atherosclerotic lesions and have been shown to express TGF-ß1 (transforming growth factor β1) and its receptors, it has so far not been experimentally addressed whether the pleiotropic cytokine TGF-ß1 may influence atherogenesis by a macrophage specific mechanism. We developed transgenic mice with macrophage specific TGF-ß1 overexpression, crossed the transgenics to the atherosclerotic ApoE (apolipoprotein E) knock-out strain and quantitatively analyzed both atherosclerotic lesion development and composition of the resulting double mutants. Compared with control ApoE(-/-) mice, animals with macrophage specific TGF-ß1 overexpression developed significantly less atherosclerosis after 24 weeks on the WTD (Western type diet) as indicated by aortic plaque area en face (p<0.05). Reduced atherosclerotic lesion development was associated with significantly less macrophages (p<0.05 after both 8 and 24 weeks on the WTD), significantly more smooth muscle cells (SMCs; p<0.01 after 24 weeks on the WTD), significantly more collagen (p<0.01 and p<0.05 after 16 and 24 weeks on the WTD, respectively) without significant differences of inner aortic arch intima thickness or the number of total macrophages in the mice pointing to a plaque stabilizing effect of macrophage-specific TGF-ß1 overexpression. Our data shows that macrophage specific TGF-ß1 overexpression reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice.