title: Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet-Induced Arterial Stiffening in Female Mice.
abstract: Women are especially predisposed to development of arterial stiffening secondary to obesity because of consumption of excessive calories. Enhanced activation of vascular mineralocorticoid receptors impairs insulin signaling, induces oxidative stress, inflammation, and maladaptive immune responses. We tested whether a subpressor dose of mineralocorticoid receptor antagonist, spironolactone (1 mg/kg per day) prevents aortic and femoral artery stiffening in female C57BL/6J mice fed a high-fat/high-sugar western diet (WD) for 4 months (ie, from 4-20 weeks of age). Aortic and femoral artery stiffness were assessed using ultrasound, pressurized vessel preparations, and atomic force microscopy. WD induced weight gain and insulin resistance compared with control diet-fed mice and these abnormalities were unaffected by spironolactone. Blood pressures and heart rates were normal and unaffected by diet or spironolactone. Spironolactone prevented WD-induced stiffening of aorta and femoral artery, as well as endothelial and vascular smooth muscle cells, within aortic explants. Spironolactone prevented WD-induced impaired aortic protein kinase B/endothelial nitric oxide synthase signaling, as well as impaired endothelium-dependent and endothelium-independent vasodilation. Spironolactone ameliorated WD-induced aortic medial thickening and fibrosis and the associated activation of the progrowth extracellular receptor kinase 1/2 pathway. Finally, preservation of normal arterial stiffness with spironolactone in WD-fed mice was associated with attenuated systemic and vascular inflammation and an anti-inflammatory shift in vascular immune cell marker genes. Low-dose spironolactone may represent a novel prevention strategy to attenuate vascular inflammation, oxidative stress, and growth pathway signaling and remodeling to prevent development of arterial stiffening secondary to consumption of a WD.
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.). demarcov@missouri.edu sowersj@missouri.edu.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Francisco I
authors.initials: FI
authors.lastname: Ramirez-Perez
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez-Lemus
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bender
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Mona
authors.initials: M
authors.lastname: Garro
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Zhe
authors.initials: Z
authors.lastname: Sun
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Meininger
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.).
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (V.G.D., J.H., G.J., A.R.A., M.G., M.R.H., C.M., J.R.S.), Division of Nephrology, Department of Medicine (A.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., F.I.R.-P., L.A.M.-L., Z.S., G.A.M., J.R.S.), and Department of Biomedical Sciences (S.B.B.), University of Missouri Columbia School of Medicine; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (V.G.D., J.H., G.J., A.R.A., S.B.B., M.G., M.R.H., C.M., A.W.-C., J.R.S.); and Dalton Cardiovascular Research Center, Columbia, MO (F.I.R.-P., L.A.M.-L., S.B.B., Z.S., G.A.M.). demarcov@missouri.edu sowersj@missouri.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D066273:Diet, Western / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000503:physiopathology; D007249:Inflammation / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D063177:Pulse Wave Analysis; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use*; D059289:Vascular Stiffness / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: aldosterone; obesity; spironolactone; vascular stiffness