title: Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females.
abstract: Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor β1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD-induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in female mice.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez-Lemus
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Radiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Division of Nephrology and Hypertension, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Whaley-Connell
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Domeier
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Meininger
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Katelee Barrett
authors.initials: KB
authors.lastname: Mueller
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D003971:Diastole; D066273:Diet, Western / Q000009:adverse effects*; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000235:genetics / Q000503:physiopathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D018161:Receptors, Mineralocorticoid; D011494:Protein Kinases; D058539:Phosphatidylinositol 3-Kinase
keywords: cardiovascular diseases; diet, Western; insulin resistance; obesity; receptors, mineralocorticoid