Abstract 15949: Activation of Adipose Tissue TACE/ADAM17 Leads to Coronary Microvascular Dysfunction in Older Obese Patients
Elevated inflammatory cytokine and adipokine levels, including tumor necrosis factor-α (TNF) and interleukin-6 (IL-6) is a hallmark of obesity- and aging-related cardiovascular pathologies. A disintegrin and metalloproteinase ADAM17 (TNF-α converting enzyme or TACE) regulates soluble TNF and IL-6 receptor levels. Here, we examined whether age-related changes in adipose tissue (AT)-expressed ADAM17 contributes to coronary microvascular dysfunction.
Coronary arterioles (CA, ~100 μm in diameter) from right atrial appendages and AT from mediastinal fat depots were examined ex vivo in 68 consecutive patients who underwent open-heart surgery. CA and AT was also studied in 3-month (young) and 24-month (aged) mice fed a high-fat diet (HFD). We found that bradykinin-induced dilation in human CA significantly declines with age in obese, but not in lean patients. CA dilation was reduced in aged, but not in young HFD mice, which was accompanied by elevated plasma TNF and IL-6 levels and increased ADAM17 activity in AT. A 7-day allotransplantation of AT from aged to young mice significantly increased plasma TNF levels in the young recipients, in which CA dilation became impaired. Moreover, we found that ADAM17 is predominantly expressed in microvessels within the human and mouse AT. ADAM17 activity and soluble TNF release from AT arteriole is increased in older patients, which was sufficient to impair CA dilation in a bioassay, in which the AT arteriole was serially connected to CA.
The present study identifies a novel pathological role for ADAM17 in the human and rodent adipose tissue. Our findings indicate that aging increases ADAM17 activity and soluble TNF levels in adipose tissue, which directly contributes to impaired CA dilation in older, obese patients. Support: AHA16PRE27550006.
Author Disclosures: H. Dou: None. A. Davila: None. V. Patel: None. V. Kamath: None. N. Weintraub: None. Z. Bagi: None.
- © 2016 by American Heart Association, Inc.