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Myocardial β 2 ‐adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure
Author(s) -
Rengo G,
Zincarelli C,
Femminella GD,
Liccardo D,
Pagano G,
de Lucia C,
Altobelli GG,
Cimini V,
Ruggiero D,
PerroneFilardi P,
Gao E,
Ferrara N,
Lymperopoulos A,
Koch WJ,
Leosco D
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01954.x
Subject(s) - medicine , heart failure , contractility , angiogenesis , cardiac function curve , myocardial infarction , isoprenaline , cardiology , gene delivery , perfusion , endocrinology , ventricular remodeling , genetic enhancement , chemistry , gene , stimulation , biochemistry
BACKGROUND AND PURPOSE We investigated whether β 2 ‐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 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. 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 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 AND IMPLICATION 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.