Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction

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6 Citations (Scopus)

Abstract

Objective-A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. Approach and Results-Coronary arterioles (CAs, ≈90 μm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m2) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. Conclusions-The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.

Original languageEnglish (US)
Pages (from-to)1180-1193
Number of pages14
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Adipose Tissue
Caveolin 1
Tumor Necrosis Factor-alpha
Obesity
Dilatation
Obese Mice
High Fat Diet
Arteries
Disintegrins
Atrial Appendage
Vascular Endothelium
Arterioles
Metalloproteases
ADAM17 Protein
Biological Assay
Thoracic Surgery
Endothelium
Blood Vessels
Transplantation
Cytokines

Keywords

  • adipose tissue
  • aging
  • caveolin 1
  • endothelium
  • humans
  • obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{368a146c431d4797a4eb7a08896d34a8,
title = "Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction",
abstract = "Objective-A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. Approach and Results-Coronary arterioles (CAs, ≈90 μm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m2) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. Conclusions-The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.",
keywords = "adipose tissue, aging, caveolin 1, endothelium, humans, obesity",
author = "Huijuan Dou and Attila Feher and Davila, {Alec C.} and {Romero Lucas}, {Maritza Josefina} and Patel, {Vijaykumar Surendrakant} and Kamath, {Manjeshwar Vinayak} and Gooz, {Monika Beck} and Rudic, {Radu Daniel} and Rudolf Lucas and Fulton, {David J} and Weintraub, {Neal Lee} and Zsolt Bagi",
year = "2017",
month = "6",
day = "1",
doi = "10.1161/ATVBAHA.117.309430",
language = "English (US)",
volume = "37",
pages = "1180--1193",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "6",

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T1 - Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction

AU - Dou, Huijuan

AU - Feher, Attila

AU - Davila, Alec C.

AU - Romero Lucas, Maritza Josefina

AU - Patel, Vijaykumar Surendrakant

AU - Kamath, Manjeshwar Vinayak

AU - Gooz, Monika Beck

AU - Rudic, Radu Daniel

AU - Lucas, Rudolf

AU - Fulton, David J

AU - Weintraub, Neal Lee

AU - Bagi, Zsolt

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Objective-A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. Approach and Results-Coronary arterioles (CAs, ≈90 μm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m2) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. Conclusions-The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.

AB - Objective-A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. Approach and Results-Coronary arterioles (CAs, ≈90 μm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m2) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. Conclusions-The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.

KW - adipose tissue

KW - aging

KW - caveolin 1

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KW - humans

KW - obesity

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