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Age‐related activation of ADAM17/TNF in adipose tissue leads to remote coronary microvascular dysfunction in obese patients
Author(s) -
Dou Huijuan
Publication year - 2017
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.31.1_supplement.833.3
Subject(s) - adipose tissue , bradykinin , medicine , endocrinology , endothelial dysfunction , vasodilation , tumor necrosis factor alpha , inflammation , obesity , endothelium , adipokine , receptor , leptin
A disintegrin and metalloproteinase ADAM17 (TNF‐α converting enzyme) regulates soluble TNF levels. Here, we examined whether age‐related changes in adipose tissue (AT)‐expressed ADAM17 contributes to the development of coronary microvascular dysfunction (CMD) in obesity. Human coronary arterioles (CA,~100 μm) and mediastinal AT were examined in patients who underwent open‐heart surgery. CA and AT were also studied in young (6‐month) and aged (24‐month) mice fed a 12‐week high‐fat‐diet (HFD). We found that bradykinin‐induced dilation in isolated human CA significantly declines with age in obese, but not lean patients. Similarly, CA dilation was reduced in aged HFD mice when compared to young. The impaired CA dilation was accompanied by increased ADAM17 activity in AT and elevated serum TNF levels. Transplantation of AT from aged HFD to young mice increased plasma TNF levels and impaired CA dilation in the young recipient mice. In patients we found an age‐related increase in AT ADAM17 activity, which was attributed to expression of ADAM17 in the vascular endothelium of AT, but not adipocytes. Excess release of TNF from AT arteries in older patients was sufficient to impair vasodilator function in a bioassay in which the AT artery was serially connected to a CA. The present study demonstrates age‐related increases in vascular endothelial ADAM17 activity and soluble TNF release in the human and rodent AT, which may contribute to the development of CMD in older obese patients. Support or Funding Information AHA16PRE27550006