Myocardial β2-adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure

G. Rengo, C. Zincarelli, G. D. Femminella, D. Liccardo, G. Pagano, C. De Lucia, G. G. Altobelli, V. Cimini, D. Ruggiero, P. Perrone-Filardi, E. Gao, N. Ferrara, A. Lymperopoulos, W. J. Koch, D. Leosco

Research output: Contribution to journalArticlepeer-review

Abstract

Background and purpose We investigated whether β2- adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. Experimental Approach We explored the angiogenic effects of β2- adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated β2-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 β2-adrenoceptor -/- mice undergoing MI. KEy 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 β2-adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-β2-adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, β2-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 β2-adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In β2-adrenoceptor-/- mice, we found a a 25% reduction in cardiac capillary density compared with β2-adrenoceptor+/+ mice. The lack of β2-adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls. CONCLUSIONS AND IMPLICATION β2- 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.

Original languageEnglish
Pages (from-to)2348-2361
Number of pages14
JournalBritish Journal of Pharmacology
Volume166
Issue number8
DOIs
Publication statusPublished - Aug 2012

Keywords

  • β-adrenoceptor
  • angiogenesis
  • gene therapy
  • heart failure
  • remodelling

ASJC Scopus subject areas

  • Pharmacology

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