title: SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.
abstract: BACKGROUND
  Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available, and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in endothelial nitric oxide synthase null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in preclinical models of pulmonary hypertension.
  
  
  RESULTS
  To evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a 2-hit PH-HFpEF model in rats with multiple features of metabolic syndrome attributable to double-leptin receptor defect (obese ZSF1) with the combined treatment of vascular endothelial growth factor receptor blocker SU5416. Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling. The glucose-lowering effect of nitrite was abolished in SIRT3-deficient human skeletal muscle cells, and in SIRT3 knockout mice fed a high-fat diet, as well. Skeletal muscle biopsies from humans with metabolic syndrome after 12 weeks of oral sodium nitrite and nitrate treatment (IND#115926) displayed increased activation of SIRT3 and AMP-activated protein kinase. Finally, early treatments with nitrite and metformin at the time of SU5416 injection reduced pulmonary pressures and vascular remodeling in the PH-HFpEF model with robust activation of skeletal muscle SIRT3 and AMP-activated protein kinase.
  
  
  CONCLUSIONS
  These studies validate a rodent model of metabolic syndrome and PH-HFpEF, suggesting a potential role of nitrite and metformin as a preventative treatment for this disease.
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lai
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Diana M
authors.initials: DM
authors.lastname: Tabima
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: John J
authors.initials: JJ
authors.lastname: Dube
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Kara S
authors.initials: KS
authors.lastname: Hughan
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Vanderpool
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Goncharov
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Elena A
authors.initials: EA
authors.lastname: Goncharova
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
authors.affiliation: From Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.). gladwinmt@upmc.edu.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D056566:Sirtuin 3 / Q000378:metabolism*; D012977:Sodium Nitrite / Q000494:pharmacology / Q000627:therapeutic use; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology*
chemical_list: C525046:Sirt3 protein, mouse; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3; D012977:Sodium Nitrite
keywords: AMP-activated protein kinases; SIRT3 protein; heart failure; hypertension, pulmonary; metabolic syndrome
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