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

Abstract

BACKGROUND AND PURPOSEWe investigated whether b2-adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. EXPERIMENTAL APPROACHWe explored the angiogenic effects of b2-adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated b2-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 b2-adrenoceptor -/-mice undergoing MI. KEY RESULTSTransgenes 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 b2-adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-b2-adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, b2-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 b2-adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In b2-adrenoceptor-/-mice, we found a~25% reduction in cardiac capillary density compared with b2-adrenoceptor+/+ mice. The lack of b2-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 IMPLICATIONb2-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.

Vascular Endothelial Growth Factor Blockade Prevents the Beneficial Effects of β-Blocker Therapy on Cardiac Function, Angiogenesis, and Remodeling in Heart Failure

“…Previously, we have shown that exercise training, independently from HRR, is able to induce VEGF upregulation and Akt activation in the post-ischemic heart (22) and to improve age-dependent VEGF downregulation and angiogenesis responses to hindlimb ischemia (26). Moreover, 2AR overexpression in the failing heart is able to enhance neoangiogenesis inducing a sustained and coordinated Akt and VEGF activation (21). The involvement of 2AR in the neoangiogenic processes in response to ischemia prompted us to use in this study a selective 1AR blocker, in order to not interfere with 2AR.…”

Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves 2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia

“…At the molecular level, it is known that the b 2 -adrenergic receptor (b 2 AR), the most abundant b adrenergic receptor (bAR) isoform in ECs, is involved in the control of these functions (Howell et al, 1988). However, ischemia can result in increased sympathetic catecholamine levels that can cause b 2 AR signaling dysfunction in ECs, resulting in an inadequate angiogenic response and loss of tissue integrity and/or function (Iaccarino et al, 2005;Rengo et al, 2012).…”

Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study

“…Finally, although a more exhaustive evaluation of all neurohormonal activation indexes (i.e. plasma norephinephrine, components of the renin-angiotensin system) [38] are lacking, NT-proBNP is widely recognized as a key component of neurohormonal activation pattern [39]. Despite the afore mentioned limitations, this study has several unique strengths.…”