title: Effects of adiponectin on calcium-handling proteins in heart failure with preserved ejection fraction.
abstract: BACKGROUND
  Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no therapeutic options for HFpEF. Adiponectin, an adipocyte-derived cytokine, exerts cardioprotective actions, and its deficiency is implicated in the development of hypertension and HF with reduced ejection fraction. Similarly, adiponectin deficiency in HFpEF exacerbates left ventricular hypertrophy, diastolic dysfunction, and HF. However, the therapeutic effects of adiponectin in HFpEF remain unknown. We sought to test the hypothesis that chronic adiponectin overexpression protects against the progression of HF in a murine model of HFpEF.
  
  
  RESULTS
  Adiponectin transgenic and wild-type mice underwent uninephrectomy, a continuous saline or d-aldosterone infusion and given 1.0% sodium chloride drinking water for 4 weeks. Aldosterone-infused wild-type mice developed HFpEF with hypertension, left ventricular hypertrophy, and diastolic dysfunction. Aldosterone infusion increased myocardial oxidative stress and decreased sarcoplasmic reticulum Ca(2+)-ATPase protein expression in HFpEF. Although total phospholamban protein expression was unchanged, there was a decreased expression of protein kinase A-dependent phospholamban phosphorylation at Ser16 and CaMKII (Ca(2+)/calmodulin-dependent protein kinase II)-dependent phospholamban phosphorylation at Thr17. Adiponectin overexpression in aldosterone-infused mice ameliorated left ventricular hypertrophy, diastolic dysfunction, lung congestion, and myocardial oxidative stress without affecting blood pressure and left ventricular EF. This improvement in diastolic dysfunction parameters in aldosterone-infused adiponectin transgenic mice was accompanied by the preserved protein expression of protein kinase A-dependent phosphorylation of phospholamban at Ser16. Adiponectin replacement prevented the progression of aldosterone-induced HFpEF, independent of blood pressure, by improving diastolic dysfunction and by modulating cardiac hypertrophy.
  
  
  CONCLUSIONS
  These findings suggest that adiponectin may have therapeutic effects in patients with HFpEF.
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.).
authors.forename: Komei
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.).
authors.forename: Richard M
authors.initials: RM
authors.lastname: Wilson
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.).
authors.forename: Eric E
authors.initials: EE
authors.lastname: Essick
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.).
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Duffen
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.).
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.).
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.affiliation: From the Whitaker Cardiovascular Institute (K.T., R.M.W., E.E.E., J.L.D., N.O., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (P.E.S.). flora.sam@bmc.org.
authors.forename: Flora
authors.initials: F
authors.lastname: Sam
mesh_terms: D052242:Adiponectin / Q000378:metabolism* / Q000627:therapeutic use; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D054459:Elasticity Imaging Techniques; D006333:Heart Failure / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D052242:Adiponectin; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D000450:Aldosterone; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium
keywords: adiponectin; calcium-binding proteins; heart failure, diastolic; hypertrophy, left ventricular; oxidative stress