Abstract 200: Low Dose Spironolactone Treatment Prevents Cardiac Diastolic Dysfunction, Oxidant Stress and Fibrosis in a Female Model of Obesity in Concert with a Modulation of Inflammation
Obesity is a global epidemic with 1.5 billion overweight or obese people worldwide. The association of obesity and a high-fat/high-fructose Western diet (WD) markedly increases cardiovascular disease (CVD) particularly diastolic dysfunction in women. Few treatments exist for diastolic heart disease but, recent work implicates the mineralocorticoid receptor (MR) in inflammation, fibrosis and oxidant stress. We thus hypothesized that low-dose spironolactone (LDSp) could prevent diastolic dysfunction by reducing fibrosis, oxidant stress and inflammation. To test this hypothesis, we developed a female model of obesity induced diastolic dysfunction and examined preventative treatment with LDSp.
Four week-old C57BL6/J female mice were fed a WD with/without 1.0mg/kg/day of Sp (n=7 for each group). This dose of LDSp exerts no effect on blood pressure. After 16 weeks, we conducted detailed phenotypic analysis and assessed diastolic function by cardiac MRI. Immunohistochemistry was also done for cardiac oxidant stress, fibrosis, collagen content and insulin receptor (IRS-1) expression. Flow cytometry of heart tissue was utilized to examine inflammatory mechanisms.
We found WD feeding caused diastolic dysfunction that was prevented by LDSp (LV diastolic relaxation time 33.4 ± 1.2ms for WD, 20.6 ± 1.5ms for control and 24.3 ± 0.9ms for WD+LDSp, p <0.01). 3-nitrotyrosine staining showed significant cardiac oxidant stress with WD feeding that was ameliorated by LDSp. Cardiac fibrosis and the collagen 1:3 ratio were markedly increased with WD but prevented by LDSp. IRS-1 expression and phosphorylation were markedly reduced by WD feeding but not improved by LDSp. Flow cytometry showed evidence towards reduced M2 macrophage polarization with lower CD11b/CD301 double positive cells in WD fed hearts with trend toward improvement with LDSp.
These findings suggest WD induces cardiac diastolic dysfunction in females by increasing oxidant stress and fibrosis potentially mediated by deficiency in anti-inflammatory M2 macrophages. MR antagonism with spironolactone may prevent the decrease in M2 macrophage polarization reducing oxidant stress and fibrosis. This work supports a novel mechanism for spironolactone in treatment of WD induced heart disease.
Author Disclosures: B. Bostick: None. J. Habibi: None. S.C. McKarns: None. L. Ma: None. N.T. Rehmer: None. S. Bender: None. M. Garro: None. A. Meuth: None. R. Nistala: None. G. Jia: None. J.R. Sowers: None.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2014 by American Heart Association, Inc.