Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice.
Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-beta1, -beta2, and -beta3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-beta in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-beta signaling using a neutralizing anti-TGF-beta1, -beta2, and -beta3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-beta signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-beta in atherosclerosis.
Mallat
Z
Z
Institut National de la Santé et de la Recherche Médicale, INSERM U541, France.
Gojova
A
A
Marchiol-Fournigault
C
C
Esposito
B
B
Kamaté
C
C
Merval
R
R
Fradelizi
D
D
Tedgui
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D008076:Cholesterol, HDL / Q000097:blood; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D003094:Collagen