title: Myocardial β(2) -adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure.
abstract: OBJECTIVE
  We investigated whether β(2) -adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart.
  
  
  METHODS
  We explored the angiogenic effects of β(2) -adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated β(2) -adrenoceptor overexpression was obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to β(2) -adrenoceptor -/- mice undergoing MI.
  
  
  RESULTS
  Transgenes were robustly expressed in the LV at 2 weeks post-gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac β(2) -adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-β(2) -adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, β(2) -adrenoceptor overexpression was associated with a markedly increased capillary and arteriolar length density and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac β(2) -adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In β(2) -adrenoceptor-/- mice, we found a ~25% reduction in cardiac capillary density compared with β(2) -adrenoceptor+/+ mice. The lack of β(2) -adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls.
  
  
  CONCLUSIONS
  β(2) -Adrenoceptors play an important role in the regulation of the angiogenic response in HF. The activation of VEGF/PKB/eNOS pathway seems to be strongly involved in this mechanism.
authors.affiliation: Salvatore Maugeri Foundation, IRCCS, Telese Terme (BN), Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rengo
authors.forename: C
authors.initials: C
authors.lastname: Zincarelli
authors.forename: G D
authors.initials: GD
authors.lastname: Femminella
authors.forename: D
authors.initials: D
authors.lastname: Liccardo
authors.forename: G
authors.initials: G
authors.lastname: Pagano
authors.forename: C
authors.initials: C
authors.lastname: de Lucia
authors.forename: G G
authors.initials: GG
authors.lastname: Altobelli
authors.forename: V
authors.initials: V
authors.lastname: Cimini
authors.forename: D
authors.initials: D
authors.lastname: Ruggiero
authors.forename: P
authors.initials: P
authors.lastname: Perrone-Filardi
authors.forename: E
authors.initials: E
authors.lastname: Gao
authors.forename: N
authors.initials: N
authors.lastname: Ferrara
authors.forename: A
authors.initials: A
authors.lastname: Lymperopoulos
authors.forename: W J
authors.initials: WJ
authors.lastname: Koch
authors.forename: D
authors.initials: D
authors.lastname: Leosco
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D015425:Myocardial Reperfusion; D009206:Myocardium; D018919:Neovascularization, Physiologic; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D020257:Ventricular Remodeling
chemical_list: D018343:Receptors, Adrenergic, beta-2