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Adipose Tissue Constituents and the Adipokine Resistin Impair Vascular Endothelial Function in Obesity via Elevated Arginase Activity
Author(s) -
Atawia Reem T.,
Chen Jijun,
Toque Haroldo A.,
Yiew Kan Hui,
Caldwell Ruth B.,
Caldwell Robert W.
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.1065.10
Subject(s) - adipokine , resistin , adipose tissue , arginase , endothelial dysfunction , medicine , endocrinology , adipocyte , adipose tissue macrophages , obesity , insulin resistance , biology , white adipose tissue , arginine , biochemistry , amino acid
Objective Define the molecular mechanisms underlying obesity‐induced endothelial dysfunction with an emphasis on the role of arginase (ARG) as a target for the better management of disease progression. Introduction Arginase (ARG) is expressed in endothelial cells (EC) in 2 isoforms (ARG1 and ARG2) and can contribute to vascular and endothelial dysfunction by limiting arginine availability for nitric oxide (NO) synthesis. Obesity is an important factor in several cardiovascular comorbidities and is associated with vascular endothelial dysfunction. Obesity is characterized by adipose tissue dysregulation resulting in increased secretion of pro‐inflammatory cytokines and adipokines such as resistin, which induces insulin resistance and endothelial dysfunction. Mechanisms underlying adipose tissue dysregulation‐induced endothelial dysfunction is not well understood. Methods To determine the effect of obesity on adipocyte dysregulation, mature adipocytes were extracted from visceral adipose tissues of diet‐induced obese (DIO) and lean mice to determine gene expression of pro‐inflammatory cytokines and adipokines. Additionally, Mouse aortic endothelial cells (MAEC) and aortic rings from lean mice were exposed to conditioned media (CM) prepared from visceral adipose tissues of DIO and lean mice or resistin (100 ηg/ml) for 24 hr to assess endothelial and vascular functions. Results Adipocytes from DIO mice showed increased mRNA expression of the pro‐inflammatory cytokines (TNF‐α and MCP‐1) and the adipokine resistin, compared to lean mice cells. MAEC exposed to CM from DIO mice showed increased mRNA expression of ARG1 and ARG2 (34% and 77%, respectively, p<0.05) accompanied by decreased NO production by 32%, p<0.01. Aortic rings incubated with CM from DIO mice exhibited a marked reduction in endothelium‐dependent vasorelaxation (EDV) to acetylcholine and increased contractile responses to phenylephrine (PE). Moreover, CM from DIO mice caused a 143% increase in resistin levels compared to CM from lean mice. Exposure of MAEC to resistin resulted in increased expression of ARG1 mRNA and decreased NO production (30% and 39%, respectively, p<0.05). Exposure of aortic rings to resistin impaired EDV. These dysfunctions were largely prevented by co‐treatment with the specific ARG inhibitor ABH (100 μM). The resistin‐induced increase in ARG1 expression in MAEC involves activation of the p38 mitogen‐activated protein kinase pathway as co‐treatment with p38 inhibitor (SB202190) prevented both effects in response to resistin. Conclusion Adipose tissue constituents from DIO mice and the pro‐inflammatory adipokine resistin impair EC‐dependent vasorelaxation via elevated arginase expression/activity Support or Funding Information NIH Grant EY11766 & NIH HL70215