title: Uric acid promotes left ventricular diastolic dysfunction in mice fed a Western diet.
abstract: The rising obesity rates parallel increased consumption of a Western diet, high in fat and fructose, which is associated with increased uric acid. Population-based data support that elevated serum uric acids are associated with left ventricular hypertrophy and diastolic dysfunction. However, the mechanism by which excess uric acid promotes these maladaptive cardiac effects has not been explored. In assessing the role of Western diet-induced increases in uric acid, we hypothesized that reductions in uric acid would prevent Western diet-induced development of cardiomyocyte hypertrophy, cardiac stiffness, and impaired diastolic relaxation by reducing growth and profibrotic signaling pathways. Four-weeks-old C57BL6/J male mice were fed excess fat (46%) and fructose (17.5%) with or without allopurinol (125 mg/L), a xanthine oxidase inhibitor, for 16 weeks. The Western diet-induced increases in serum uric acid along with increases in cardiac tissue xanthine oxidase activity temporally related to increases in body weight, fat mass, and insulin resistance without changes in blood pressure. The Western diet induced cardiomyocte hypertrophy, myocardial oxidative stress, interstitial fibrosis, and impaired diastolic relaxation. Further, the Western diet enhanced activation of the S6 kinase-1 growth pathway and the profibrotic transforming growth factor-β1/Smad2/3 signaling pathway and macrophage proinflammatory polarization. All results improved with allopurinol treatment, which lowered cardiac xanthine oxidase as well as serum uric acid levels. These findings support the notion that increased production of uric acid with intake of a Western diet promotes cardiomyocyte hypertrophy, inflammation, and oxidative stress that lead to myocardial fibrosis and associated impaired diastolic relaxation.
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Brian P
authors.initials: BP
authors.lastname: Bostick
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.).
authors.forename: Adam T
authors.initials: AT
authors.lastname: Whaley-Connell
authors.affiliation: From the Division of Endocrinology and Metabolism, Department of Medicine (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), Division of Nephrology and Hypertension, Department of Medicine (A.T.W.-C.), Department of Medical Pharmacology and Physiology (V.G.D., J.R.S.), Diabetes and Cardiovascular Center (G.J., J.H., B.P.B., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.), and Department of Radiology (L.M.), University of Missouri School of Medicine, Columbia; and Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (G.J., J.H., B.P.B., L.M., V.G.D., A.R.A., M.R.H., A.T.W.-C., J.R.S.). sowersj@health.missouri.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D066273:Diet, Western / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects; D019422:Dietary Sucrose / Q000009:adverse effects; D004195:Disease Models, Animal; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000209:etiology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014527:Uric Acid / Q000097:blood*; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000209:etiology* / Q000503:physiopathology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004041:Dietary Fats; D019422:Dietary Sucrose; D014527:Uric Acid; D000493:Allopurinol; D014969:Xanthine Oxidase