title: Increased beta2-adrenoceptors in doxorubicin-induced cardiomyopathy in rat.
abstract: BACKGROUND
  The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model.
  
  
  METHODS
  Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg x kg(-1)) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific β-AR stimulations at d35.
  
  
  RESULTS
  At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β3-AR expression was only decreased at d70 (-37±8%). At d35, β1-AR expression was decreased by 68±6%, but ex vivo β1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β2-AR response in Dox-CM hearts, suggesting a decoupling of β2-AR to Gi protein.
  
  
  CONCLUSIONS
  This study highlights the β1/β2-AR imbalance in early Dox-CM and reveals the important role that β2-AR/Gi coupling could play in this pathology. Our results suggest that β2-AR could be an interesting target at early stage of Dox-CM.
authors.affiliation: l'institut du thorax, Unité Inserm UMR 1087/CNRS UMR 6291, Nantes, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Merlet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Piriou
authors.forename: Bertrand
authors.initials: B
authors.lastname: Rozec
authors.forename: Amandine
authors.initials: A
authors.lastname: Grabherr
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lauzier
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Trochu
authors.forename: Chantal
authors.initials: C
authors.lastname: Gauthier
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004317:Doxorubicin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D005576:Colforsin; D004317:Doxorubicin; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol