Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice.
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.
Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, Missouri;
Brian
B
Bostick
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Javad
J
Habibi
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Vincent G
VG
DeMarco
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Guanghong
G
Jia
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri;
Timothy L
TL
Domeier
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri;
Michelle D
MD
Lambert
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Annayya R
AR
Aroor
Division of Nephrology, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Ravi
R
Nistala
Department of Biomedical Sciences, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and Dalton Cardiovascular Research Center, Columbia, Missouri.
Shawn B
SB
Bender
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Mona
M
Garro
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Melvin R
MR
Hayden
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Lixin
L
Ma
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and.
Camila
C
Manrique
Division of Endocrinology, Diabetes and Metabolism, University of Missouri, Columbia, Missouri; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri; and Dalton Cardiovascular Research Center, Columbia, Missouri Department of Radiology, University of Missouri, Columbia, Missouri; sowersj@missouri.edu.
James R
JR
Sowers
D000818:Animals; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D003971:Diastole / Q000187:drug effects*; D059305:Diet, High-Fat; D066273:Diet, Western; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005632:Fructose; D006352:Heart Ventricles / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D013148:Spironolactone / Q000008:administration & dosage*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D019422:Dietary Sucrose; D018836:Inflammation Mediators; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D005632:Fructose; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse
aldosterone; cardiac hypertrophy; high-fat diet; high-fructose diet; inflammation; low-dose spironolactone; mineralocorticoid antagonism; myocardial compliance; oxidative stress