title: Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function.
abstract: BACKGROUND
  Both the A1- and A3-adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A1-AR and A3-AR is associated with changes in the cardiac phenotype. To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A1-AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter.
  
  
  RESULTS
  Constitutive A1-AR overexpression caused the development of cardiac dilatation and death within 6 to 12 weeks. These mice developed diminished ventricular function and decreased heart rate. In contrast, when A1-AR expression was delayed until 3 weeks of age, mice remained phenotypically normal at 6 weeks, and >90% of the mice survived at 30 weeks. However, late induction of A1-AR still caused mild cardiomyopathy at older ages (20 weeks) and accelerated cardiac hypertrophy and the development of dilatation after pressure overload. These changes were accompanied by gene expression changes associated with cardiomyopathy and fibrosis and by decreased Akt phosphorylation. Discontinuation of A1-AR induction mitigated cardiac dysfunction and significantly improved survival rate.
  
  
  CONCLUSIONS
  These data suggest that robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy, whereas delaying A1-AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A1-AR transgenic mouse model provides novel insights into the role of adenosine signaling in heart failure and illustrates the potentially deleterious consequences of selective versus nonselective activation of adenosine-signaling pathways in the heart.
authors.affiliation: Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Funakoshi
authors.forename: Tung O
authors.initials: TO
authors.lastname: Chan
authors.forename: Julie C
authors.initials: JC
authors.lastname: Good
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Libonati
authors.forename: Jarkko
authors.initials: J
authors.lastname: Piuhola
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Scott M
authors.initials: SM
authors.lastname: MacDonnell
authors.forename: Ling L
authors.initials: LL
authors.lastname: Lee
authors.forename: David E
authors.initials: DE
authors.lastname: Herrmann
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Martini
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D004318:Doxycycline / Q000494:pharmacology; D004452:Echocardiography; D004562:Electrocardiography; D005355:Fibrosis; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D043682:Receptor, Adenosine A1; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline