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Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice.

Abstract
Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg·kg(-1)·day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (<Tei index) and septal annular velocity (<E'-to-A' ratio), as assessed by echocardiography, as well as decreased diastolic relaxation time/increased diastolic initial filling rate, as assessed by MRI. The relationship between passive sarcomere length of cardiac myocytes and ventricular pressure was monitored using di-8-ANEPPS staining of the t-tubule network in hearts ex vivo. Sp administration led to longer sarcomere lengths at each pressure indicative of improved ventricular compliance in WD-fed mice. Sp also prevented left ventricular hypertrophy, interstitial fibrosis, and oxidative stress. Sp prevented the WD-induced increased expression of myocardial proinflammatory M1 macrophage markers monocyte chemoattractant protein-1 and CD11c and increased the expression of the anti-inflammatory M2 macrophage marker CD206. These findings demonstrate that WD-induced DD is associated with increased oxidant stress, fibrosis, and immune dysregulation. Mineralocorticoid receptor antagonism enhanced M2 macrophage polarization and ameliorated oxidant stress and fibrosis. This work supports a novel blood pressure-independent effect of MR antagonism as a strategy to prevent diet-induced DD in women. Mineralocorticoid antagonism; low-dose spironolactone; aldosterone;high-fat diet; high-fructose diet; oxidative stress; inflammation; cardiac hypertrophy; myocardial compliance.
AuthorsBrian Bostick, Javad Habibi, Vincent G DeMarco, Guanghong Jia, Timothy L Domeier, Michelle D Lambert, Annayya R Aroor, Ravi Nistala, Shawn B Bender, Mona Garro, Melvin R Hayden, Lixin Ma, Camila Manrique, James R Sowers
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 308 Issue 9 Pg. H1126-35 (May 01 2015) ISSN: 1522-1539 [Electronic] United States
PMID25747754 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2015 the American Physiological Society.
Chemical References
  • Dietary Sucrose
  • Inflammation Mediators
  • Mineralocorticoid Receptor Antagonists
  • Receptors, Mineralocorticoid
  • Spironolactone
  • Fructose
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
Topics
  • Animals
  • Cardiomegaly (pathology, physiopathology, prevention & control)
  • Diastole (drug effects)
  • Diet, High-Fat
  • Diet, Western
  • Dietary Sucrose
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Fructose
  • Heart Ventricles (drug effects, immunology, metabolism, pathology, physiopathology)
  • Inflammation Mediators (metabolism)
  • Mice, Inbred C57BL
  • Mineralocorticoid Receptor Antagonists (administration & dosage)
  • Myocytes, Cardiac (drug effects, metabolism)
  • Oxidative Stress (drug effects)
  • Receptors, Mineralocorticoid (drug effects, metabolism)
  • Ribosomal Protein S6 Kinases, 90-kDa (metabolism)
  • Sarcomeres (drug effects, metabolism)
  • Sex Factors
  • Spironolactone (administration & dosage)
  • Time Factors
  • Ventricular Dysfunction, Left (etiology, immunology, metabolism, pathology, physiopathology, prevention & control)
  • Ventricular Function, Left (drug effects)
  • Ventricular Pressure (drug effects)
  • Ventricular Remodeling (drug effects)

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