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Deficiency for Smooth Muscle‐specific Insulin‐like Growth Factor I (IGF‐1) Receptor Increases Atherosclerotic Plaque Size and Promotes Plaque Destabilization
Author(s) -
Sukhanov Sergiy,
Higashi Yusuke,
Snarski Patricia,
Delafontaine Patrick
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.722.3
Subject(s) - tunel assay , medicine , endocrinology , receptor , masson's trichrome stain , growth factor , insulin like growth factor , apoptosis , chemistry , immunohistochemistry , biology , biochemistry
We have previously shown that systemic insulin‐like growth factor I (IGF‐1) infusion reduces atherosclerosis in Apoe‐null mice. We generated smooth muscle cells (SMC)‐specific IGF‐1 receptor (IGF‐1R)/Apoe‐double‐null mice (22KI) by crossing floxed IGF‐1R mice (FIR, control) with SM22a‐promoter‐driven Cre mice to study role of SMC IGF‐1R in atherogenesis. 22KI mice had >80% reduction in aortic IGF‐1R levels, 15±3% decrease in body weight (P<0.05) and 23±3% reduction in size of individual aortic SMC (P<0.05) suggesting that marked growth retardation seen in 22KI mice was mediated by SMC hypotrophy. 22KI mice had increase in aortic atherosclerotic plaque surface area (en face analysis, 22KI: 26±5% vs. FIR: 7±4%, P<0.001) and plaque cross‐sectional area (H&E staining, 22KI: 39±5% vs. FIR: 24±3%, P<0.05). Atherosclerotic plaque in 22KI mice had significantly reduced SMC levels (aSMA IHC: 70±3% decrease; calponin IHC: 76±3% decrease vs FIR) and increased SMC apoptosis (TUNEL assay: 2.5‐fold increase, P<0.01). 22KI's plaque had marked reduction in collagen levels (Trichrome staining, 22KI: 7±2% vs. FIR: 31±4%, P<0.05) and 4‐fold decrease in levels of collagen RNA‐binding protein LARP6. Aortic SMC isolated from 22KI mice had reduced proliferation (Edu assay), suppressed cell migration (wound healing assay) and increased sensitivity to oxidant‐induced apoptosis (TUNEL assay) and these effects were associated with inhibition of IGF‐1‐induced PI3 kinase/Akt‐dependent signaling. We quantified features of former plaque disruption in brachiocephalic artery from 22KI and FIR mice. We found that 22KI's plaque has increased number of fibrous cap breaks; elevated intraplaque hemorrhage and increased fibrin deposition suggesting reduced plaque stability. In summary, SMC‐specific IGF‐1R deficiency increased atherosclerosis and reduced atherosclerotic plaque stability. Suppression of IGF‐1‐dependent and Akt‐mediated signaling may mediate pro‐atherogenic SMC phenotype in 22KI mice. These data established importance of SMC IGF‐1 signaling for atheroprotection. Support or Funding Information NIH/NHLBI