Abstract 74: The Nox4 Inhibitor GKT137831, Prevents Aldosterone Production by Adipocytes and Protects Against Adipose Tissue Inflammation and Fibrosis in Obese Mice

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Aldosterone (aldo) plays an important role in obesity-associated cardiovascular risk. We demonstrated that aldo is produced by adipocytes, an effect associated with increased generation of reactive oxygen species (ROS). These processes are exaggerated in obesity. The relationship between adipocyte aldosterone and ROS is unclear. We postulated that Nox4-derived ROS is important for aldo production in adipocytes and leads to a pro-inflammatory phenotype in obesity. Studies were performed in db/m (lean) and db/db (obese) mice, treated with low (20mg/kg/day) or high dose (60mg/kg/day) GKT137831 (GKT, Nox4 inhibitor, 16 weeks). Epididymal (EVAT) and perivascular (PVAT) fat were collected. Plasma and adipocyte aldo were measured by ELISA. Adipose tissue fibrosis was evaluated by picro Sirius red staining and inflammatory mediators by immunostudies. Body weight was increased in db/db mice (61.8g vs control 33.5g), with no effect of GKT. Epididymal adiposity was increased in db/db mice (0.098g vs. 0.067g, p<0.05). Plasma aldo levels in db/db (pg/mL: 518 vs. 272g) and aldo levels in culture media from db/db adipocytes were increased (pg/mL/μg RNA: 1964 vs. 388), p<0.05. All effects decreased by high dose GKT. In PVAT, CYP11B2 gene expression was increased in db/db (2.6±0.8 vs control 1.1±0.1, p<0.05), an effect blocked by Nox4 inhibition. Gene expression of adipocyte differentiation marker, AP2, was increased (3.5±1.1 vs control 1.4±0.4) while anti-inflammatory marker adiponectin was decreased (0.7±0.1 vs control 1.3±0.2, p<0.05)) in obese mice. GKT decreased AP2 levels. Adipocyte-derived TNFα was increased in db/db (4.9±1.8 vs control 1.6±0.6, p<0.05), an effect blocked by GKT. Pro-collagen I, marker of fibrosis, was increased in db/db mice (132±11 vs control 87±4, p<0.05). Sirius red staining was exaggerated in EVAT from db/db mice, and decreased by Nox4 inhibition. In conclusion, Nox4 plays a role in regulating adipocyte-derived aldosterone and promotes a pro-inflammatory and profibrotic adipose phenotype in obese db/db mice. These findings suggest that adipocyte Nox4 links hyperaldosteronism and inflammation/fibrosis in adiposity and as such may be a putative therapeutic target for obesity-associated cardiovascular damage.

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