Abstract 367: A Nox4 Inhibitor, GKT 137831, Decreases Aldosterone Synthesis, Adiposity and Vascular Contractility in a Murine Model of Diabetes.
Nox4 is expressed in many cell types including vascular cells and adipocytes. Expression of Nox4 is increased in cardiovascular diseases, such as hypertension and diabetes. Despite the advancement in the understanding of Nox4 biochemistry and its mechanisms of regulation, the pathophysiological role of Nox4 remains elusive and controversial. We recently demonstrated that adipocytes produce aldosterone, an effect that was exacerbated in diabetes and contributed to vascular dysfunction. Here we postulated that Nox4 plays a role on adipocyte-derived aldosterone production, leading to vascular dysfunction, during diabetes. Studies were performed in db/m (control) and db/db mice (a murine model of diabetes). Control and db/db mice were divided into 3 groups: Group 1, no treatment, Group 2, treatment with 20 mg (low dose) and Group 3, 60 mg (high dose) of GKT137831 (GKT) (Nox4 inhibitor) for 16 weeks. Blood pressure was measured by tail-cuff. Aldosterone (aldo) levels were measured in plasma and cell culture media from mature adipocytes extracted from all groups. Mesenteric arteries were obtained from all groups to study vascular responses to acetylcholine, a nitric oxide donor (DEA-NO) and norepinephrine (NE) by myography. Body weight was increased in db/db (61.8g ± 0.95) versus control (33.5g ± 0.72) mice, p<0.05. GKT treatment did not alter body weight in db/m or db/db mice. Blood pressure levels were similar in all groups. Epididymal adiposity was increased in db/db mice (0.098g ± 0.16 vs. 0.067g ± 0.15, p<0.05). Aldo levels were increased in plasma (pg/mL: 518 ± 67 vs. 272 ± 30, p<0.05) and media from mature adipocytes (pg/mL/μg RNA: 1964 ± 213 vs. 388 ± 55, p<0.001). GKT treatment (high dose) decreased adiposity (0.07g ± 0.05) and aldo levels in plasma (390 ± 41 pg/mL) and media from mature adipocytes (577 ± 91 pg/mL), p<0.01. Endothelial dysfunction observed in db/db mice was not affected by GKT treatment. However, GKT treatment induced a decrease on NE-induced contraction in mesenteric arteries from db/db mice (pD2 values: db/db vs. db/db high dose, 6.4±0.1 vs. 5.6 ± 0.1, p<0.001). Our findings suggest a role for Nox4 in adipocyte-derived aldo production and vascular reactivity in db/d mice. Such Nox4-related processes may be important in obesity-diabetes.
- © 2012 by American Heart Association, Inc.