Abstract 012: Mineralocorticoid Receptors Mediate Western Diet-Induced Macrophage Polarization and Aortic Stiffness
Mineralocorticoid receptors (MRs) are expressed in vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells (ECs) and signaling through these receptors may play a key role in development of aortic stiffness. Accordingly, we hypothesized that these vascular MRs are involved in the western diet (WD) - induced macrophage polarization and aortic stiffness. The stiffness of primary cultured VSMC and tissue ECs or VSMCs from mice was measured using cell nano-indentation with atomic force microscopy (AFM). Both Ang II (100 nM) and aldosterone (10 nM) increased VSMC stiffness in vitro. Also, B57 mice fed a WD for 16 weeks increased EC and VSMC stiffness as determined by in vivo pulse wave velocity and ex vivo AFM techniques. The elevated aortic stiffness was accompanied by increased mRNA expression of M1 markers MCP-1, CD 86, and CD11b. However, treatment with low dose spironolactone (Sp) (1.0 mg/kg/day), a dose not affecting blood pressure, significantly attenuated WD-induced increases in stiffness in murine ECs and VSMCs. Sp increased M2 marker IL10 and the expression ratio of M2/M1 marker genes in aorta by real time PCR. Interestingly, mice with EC MR knockout did not develop WD- induced aortic vasodilation dysfunction under both Ach and SNP (10-9-10-4 mol/L) stimulation. Furthermore, low dose Sp inhibited WD- caused up-regulation of ERK 1/2 and down-regulation Akt/eNOS signaling pathways in the aorta. These findings support the notion that increased vascular and macrophage MR signaling play a key role in macrophage polarization and associated aortic stiffness that result from consuming a WD high in fructose and fat.
Author Disclosures: G. Jia: None. A.R. Aroor: None. V.G. DeMarco: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; Boehringer Ingelheim. Z. Sun: None. B.P. Bostick: None. G.A. Meininger: None. I. Jaffe: None. J.R. Sowers: G. Consultant/Advisory Board; Modest; Merck Pharmaceuticals.
- © 2014 by American Heart Association, Inc.