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

被引：54

作者：

Rengo, G. ^{[1
,2
,3
]}

Zincarelli, C. ^{[1
,2
,3
]}

Femminella, G. D. ^{[1
]}

Liccardo, D. ^{[1
]}

Pagano, G. ^{[1
]}

de Lucia, C. ^{[1
]}

Altobelli, G. G. ^{[4
]}

Cimini, V. ^{[4
]}

Ruggiero, D. ^{[1
]}

Perrone-Filardi, P. ^{[1
]}

Gao, E. ^{[3
]}

Ferrara, N. ^{[2
]}

Lymperopoulos, A. ^{[5
]}

Koch, W. J. ^{[3
]}

Leosco, D. ^{[1
]}

机构：

[1] Univ Naples Federico II, Dept Internal Med Cardiovasc & Immunol Sci, I-80131 Naples, Italy

[2] IRCCS, Salvatore Maugeri Fdn, Telese Terme, BN, Italy

[3] Temple Univ, Ctr Translat Med, Sch Med, Philadelphia, PA 19122 USA

[4] Univ Naples Federico II, Dept Biomorphol & Funct Sci, I-80131 Naples, Italy

[5] Nova SE Univ, Dept Pharmaceut Sci, Coll Pharm, Ft Lauderdale, FL 33314 USA

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2012年 / 166卷 / 08期

关键词：

angiogenesis; heart failure; gene therapy; beta(2)-adrenoceptor; remodelling; RECEPTOR OVEREXPRESSION; EXPRESSION; GRK2; HYPERTROPHY; APOPTOSIS; NEOANGIOGENESIS; TRANSCRIPTION; TRANSDUCTION; MANIPULATION; STIMULATION;

D O I：

10.1111/j.1476-5381.2012.01954.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

BACKGROUND AND PURPOSE We investigated whether beta(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 beta(2)-adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated beta(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 beta(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 beta(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-beta(2)-adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, beta(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 beta(2)-adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In beta(2)-adrenoceptor-/- mice, we found a similar to 25% reduction in cardiac capillary density compared with beta(2)-adrenoceptor+/+ mice. The lack of beta(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 beta(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.

引用

页码：2348 / 2361

页数：14

共 47 条

[1] Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy [J].