title: ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome.
abstract: BACKGROUND
  Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.
  
  
  METHODS
  This study was performed in LDL-receptor (LDLR-/-) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR-/-, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during β-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp.
  
  
  RESULTS
  In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and β-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to β-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+.
  
  
  CONCLUSIONS
  Cardiomyocyte contractility and β-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to β-adrenergic stimulation in MS.
authors.affiliation: Department of Cardiovascular Sciences, Research Unit of Experimental Cardiac Surgery, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.
authors.forename: Ines
authors.initials: I
authors.lastname: Nevelsteen
authors.forename: Virginie
authors.initials: V
authors.lastname: Bito
authors.forename: Gerry
authors.initials: G
authors.lastname: Van der Mieren
authors.forename: Annelies
authors.initials: A
authors.lastname: Vanderper
authors.forename: An
authors.initials: A
authors.lastname: Van den Bergh
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.forename: Kanigula
authors.initials: K
authors.lastname: Mubagwa
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D000806:Angiotensin-Converting Enzyme Inhibitors