title: Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction.
abstract: Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low-dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure-independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance.
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.). benders@missouri.edu.
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bender
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Jaume
authors.initials: J
authors.lastname: Padilla
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jenkins
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Mona
authors.initials: M
authors.lastname: Garro
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pulakat
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: From the Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (S.B.B., V.G.D.M., J.H., M.G., L.P., A.R.A., J.R.S.); Department of Biomedical Sciences (S.B.B.), Dalton Cardiovascular Research Center (S.B.B., J.P., J.R.S.), and Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia; Division of Endocrinology, Diabetes and Metabolism (V.G.D.M., J.H., M.G., A.R.A., J.R.S.) and Division of Cardiovascular Medicine (L.P.), Department of Medicine, Department of Medical Pharmacology and Physiology (V.G.D.M., L.P., J.R.S.), and Department of Child Health (J.P.), University of Missouri School of Medicine, Columbia; Department of Kinesiology, University of Georgia, Athens, GA (N.T.J.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D003971:Diastole; D004195:Disease Models, Animal; D004452:Echocardiography; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009765:Obesity / Q000150:complications*; D051381:Rats; D011924:Rats, Zucker; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone
keywords: aldosterone; echocardiography; immune marker; metabolic syndrome X