Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Apolipoproteins E / physiology
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Arteriosclerosis / genetics
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Arteriosclerosis / metabolism
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Arteriosclerosis / pathology*
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Carotid Stenosis / genetics
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Carotid Stenosis / metabolism
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Carotid Stenosis / pathology
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Disease Progression
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Drug Administration Schedule
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Fibrosis
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / pharmacology
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Immunoglobulin G / administration & dosage
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Immunoglobulin G / pharmacology
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Phenotype
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / administration & dosage
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Receptors, Transforming Growth Factor beta / metabolism
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology
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Solubility
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology*
Substances
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Apolipoproteins E
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II