title: Insulin inhibits beta-adrenergic action in ischemic/reperfused heart: a novel mechanism of insulin in cardioprotection.
abstract: OBJECTIVE
  Sympathetic overactivity is closely connected with cell injury and contractile dysfunction during myocardial ischemia/reperfusion (MI/R). Insulin exerts protection for the I/R heart and the underlying mechanisms remain unclear. This study aimed to investigate the ability of insulin to modulate beta-adrenergic actions on myocardial contraction and post-ischemic injury in acute MI/R and the underlying mechanism.
  
  
  METHODS
  Isolated hearts from adult SD rats were subjected to MI/R (30 min/2 h) and treated with isoproterenol (ISO) or/and insulin. Myocardial contraction, cardiomyocyte apoptosis, myocardial injury and infarction were assessed. In a separate study, isolated ventricular myocytes were subjected to simulated I/R (15/30 min) and myocyte shortening and intracellular Ca2+ transient in response to ISO during reperfusion were assessed with presence or absence of insulin.
  
  
  RESULTS
  In isolated I/R hearts, insulin largely reversed the ISO-associated contractile functional impairment at 2 h after MI/R, inhibiting ISO-induced declines in heart rate and left ventricular systolic pressure by 34.0% and 23.0% and preventing ISO-induced elevation in left ventricular end-diastolic pressure by 28.7% respectively (all P < 0.05). In addition, ISO alone resulted in enlarged infarct size, elevated CK and LDH activity and increased apoptotic index in I/R hearts compared with vehicle, which were inhibited by treatment of insulin (all P < 0.05). Interestingly, in SI/R cardiomyocytes, insulin alone at 10(-7 )mol/l increased cell contraction whereas attenuated the positive inotropic response to ISO (10(-9 )mol/l) during R as evidenced by a 18.7% reduction in peak twitch amplitude and a 23.9% reduction in calcium transient amplitude (both P < 0.05). Moreover, insulin blunted ISO-mediated increase in PKA activity, enhanced the PKA-dependent phosphorylation of phospholamban (PLB), resulting in increased sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity.
  
  
  CONCLUSIONS
  Insulin attenuated the contractile response to beta-AR stimulation and suppressed ISO-elicited cardiac dysfunction and cell injury in MI/R. The inhibitory effect of insulin on the beta-adrenergic action involved the inhibition of PKA-mediated Ca2+ transient and promotion of post-ischemic Ca2+ handling.
authors.affiliation: Department of Cardiology and Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qiu-Jun
authors.initials: QJ
authors.lastname: Yu
authors.forename: Rui
authors.initials: R
authors.lastname: Si
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Zhang
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Guo
authors.forename: Hai-Chang
authors.initials: HC
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D000319:Adrenergic beta-Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000319:Adrenergic beta-Antagonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D007328:Insulin; D007545:Isoproterenol; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban