title: Insulin-like growth factor 1 prevents diastolic and systolic dysfunction associated with cardiomyopathy and preserves adrenergic sensitivity.
abstract: OBJECTIVE
  Insulin-like growth factor 1 (IGF-1)-dependent signalling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo therapeutic potential of IGF-1 for heart disease is not well established. Here, we test the potential therapeutic benefits of IGF-1 on cardiac function using an in vivo model of chronic catecholamine-induced cardiomyopathy.
  
  
  METHODS
  Rats were perfused with isoproterenol via osmotic pump (1 mg kg(-1) per day) and treated with 2 mg kg(-1) IGF-1 (2 mg kg(-1) per day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analysed for fibrosis and apoptosis, and relevant biochemical signalling cascades were assessed.
  
  
  RESULTS
  After 4 weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax) and structural remodelling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110α signalling and activated Akt are selectively upregulated in Iso+IGF-1-treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups; however, tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment.
  
  
  CONCLUSIONS
  IGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies.
authors.affiliation: Q-Test Labs, Columbus, OH, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Roof
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Boslett
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinarian Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Russell
authors.affiliation: Q-Test Labs, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: del Rio
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Alecusan
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Zweier
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Ziolo
authors.affiliation: Q-Test Labs, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hamlin
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Curran
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004452:Echocardiography; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002316:Cardiotonic Agents; D007334:Insulin-Like Growth Factor I; D007545:Isoproterenol
keywords: adrenergic stimulation; cardiomyopathy; diastolic dysfunction; insulin-like growth factor 1; systolic dysfunction; tetrahydrobiopterin