Abstract 14793: Obesity-induced Inflammation of the Visceral Adipose Tissue is Mediated by Upregulation of Arginase 1 in Vascular Endothelial Cells
Obesity-induced cardiovascular dysfunction involves pathological expansion of visceral adipose tissue (VAT). Our previous studies have shown that arginase 1 (A1) expression in vascular endothelial cells (EC) is critically involved in obesity-induced vascular dysfunction. Elevated arginase activity can reduce availability of L-Arginine to NO synthase, resulting in decreased NO production, oxidative stress, leukocyte attachment and vascular infiltration. Here we tested the hypothesis that EC A1 activity also drives obesity-related pathological VAT remodeling.
Our study utilized 70 wild type (WT) and EC-A1 knockout (EC-A1-KO) mice made obese by high fat/high sucrose (HFHS) diet (6 mos). In WT mice, HFHS diet increased body weight (0.4X), fasting blood glucose (0.8X), and postprandial plasma insulin (3X). The metabolic dysfunction was accompanied by significant increases in VAT mRNA expression of A1, A2 and iNOS (p<0.05) while VAT adiponectin, eNOS, and PPARγ and PGC-1α were all reduced compared with normal diet controls. HFHS diet also increased numbers of circulating inflammatory monocytes (2.1X) and expression of TNF (3.5X), MCP-1 (3.8X), VCAM-1 (1.9X). VAT infiltration by inflammatory macrophage MΦ was increased (4.1X), while reparative MΦ were reduced (0.8X). VAT morphometric analysis showed adipocyte hypertrophy, macrophage infiltration with formation of “crown-like” structures around degenerating adipocytes, along with decreased capillary density and fibrosis. These effects, except for weight gain and hyperglycemia, were all prevented or significantly reduced (p<0.05) in mice lacking EC-A1 or treated with the arginase inhibitor ABH (8 mg/kg/day). In isolated mouse aortic EC, 24 hr exposure to high glucose (25 mM) and palmitate (200 μM) reduced NO production (0.5X), increased A1, A2, TNF, ICAM-1 and MCP-1 mRNA, and increased monocyte adhesion (2.1X) (p<0.05). Deletion of EC A1 or treatment with ABH (100 μM) prevented these effects.
In conclusion, VAT inflammation induced by HFHS diet is mediated by EC A1 expression. Furthermore, activation/inflammation of ECs by high glucose and palmitate also involves A1 activity. Limiting arginase activity appears to be a therapeutic means to control obesity-induced inflammation pathology.
Author Disclosures: L. Yao: None. A. Bhatta: None. Z. Xu: None. R. Lucas: None. Y. Huo: None. Z. Bagi: None. R.B. Caldwell: None. R.W. Caldwell: None.
- © 2016 by American Heart Association, Inc.