Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

Abstract

Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of b-adrenergic receptor antagonism.

Tonic Inhibition by G Protein–Coupled Receptor Kinase 2 of Akt/Endothelial Nitric-Oxide Synthase Signaling in Human Vascular Endothelial Cells under Conditions of Hyperglycemia with High Insulin Levels

“…The relationship between up-regulated cardiac GRK2 levels and heart failure has been well established in animal models and in patients afflicted with different heart conditions (Harris et al, 2001;Reinkober et al, 2012). Moreover, it has been suggested that up-regulated expression of GRK2 in the vasculature might be associated with the pathogenesis of human essential hypertension (Gros et al, 2000;Cohn et al, 2009).…”

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

“…[120][121][122] Of interest, the persistent β-adrenergic receptor kinase carboxyl-terminus cardiac expression allowed by AAV vectors could offer major advantages versus β-blocker therapy, namely the achievement of long-term therapeutic benefits after a single treatment and the lack of unspecific blocking of β-adrenergic receptor signaling pathway in other organs. 123 An alternative promising strategy stems from the use of AAV vectors to overexpress diffusible growth factors, which can extend their effect beyond the individually transduced cells. Multiple intramyocardial injections of an AAV9 vector expressing VEGF-B, a member of the VEGF family that selectively binds VEGFR-1 expressed on cardiomyocytes, remarkably improved cardiac function in rats after myocardial infarction, 124 in mice after aortic constriction, 125 and in dogs chronically instrumented to develop tachypacing-induced dilated cardiomyopathy.…”

Peptide substrates for G protein‐coupled receptor kinase 2

“…GRK2 (formerly known as b-adrenergic receptor kinase 1) was found to be overexpressed in various brain and cardiovascular diseases, and is therefore considered to be a potential therapeutic target for these diseases [2][3][4][5]. Selective inhibition of GRK2 activity has been shown to increase therapeutic efficacies and decrease side effects [5,8].…”