Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression.
The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-beta, and a pivotal role for TGF-beta in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-beta inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-beta receptor II (TGFbetaRII:Fc), which inhibits TGF-beta signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 microg, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-beta signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGFbetaRII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGFbetaRII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-beta in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.
Lutgens
Esther
E
Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
Gijbels
Marion
M
Smook
Marjan
M
Heeringa
Peter
P
Gotwals
Philip
P
Koteliansky
Victor E
VE
Daemen
Mat J A P
MJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016893:Carotid Stenosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005355:Fibrosis; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II