In Vivo Ventricular Gene Delivery of a β-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction

Shah, Ashish S.; White, David C.; Emani, Sitaram M.; Kypson, Alan P.; Lilly, R. Eric; Wilson, Katrina H.; Glower, Donald D.; Lefkowitz, Robert J.; Koch, Walter J.

doi:10.1161/01.cir.103.9.1311

Cited by 175 publications

(111 citation statements)

References 19 publications

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“…Overexpression of bARKct in several models of heart failure has been shown to result in improved hemodynamic conditions, for example, after somatic gene transfer into rabbits with heart failure because of rapid pacing 5 or myocardial infarction. 6,7 Also, crossbreeding of cardiac-specific bARKct-transgenic mice with mouse models of heart failure due to ablation of the muscle LIM protein (MLP (À/À) mice), 8 due to a myosin heavy chain mutant 9 or due to overexpression of calsequestrin 10 prevented the development of heart failure or improved survival. This effect was additive to the treatment of heart failure with b-blockers.…”

Section: Introductionmentioning

confidence: 99%

Effects of two Gβγ-binding proteins – N-terminally truncated phosducin and β-adrenergic receptor kinase C terminus (βARKct) – in heart failure

Li¹,

Laugwitz

Pinkernell

et al. 2003

Gene Ther

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Myocardial overexpression of the C-terminus of b-adrenergic receptor kinase (bARKct) has been shown to result in a positive inotropic effect or an improvement of survival in heart failure. However, it is not clear whether this beneficial effect is mainly because of dominant-negative inhibition of bARK1, and a consecutive resensitization of b-adrenergic receptors (bAR), or rather due to inhibition of other Gbgmediated effects. In this study, we tested whether overexpression of N-terminally truncated phosducin (nt-delphosducin), another Gbg-binding protein that does not resensitize bARs owing to simultaneous inhibition of GDP release from Ga subunits, shows the same effects as bARKct. Adenoviral gene transfer was used to express ntdel-phosducin and bARKct in isolated ventricular cardiomyocytes and in myocardium of rabbits, which suffered from heart failure because of rapid ventricular pacing. bARstimulated cAMP formation was increased by bARKct, but not by nt-del-phosducin, whereas both proteins inhibited Gbg-mediated effects. Both transgenes also increased contractility of normal and failing isolated cardiomyocytes and improved contractility in rabbits with heart failure after gene transfer in vivo. In conclusion, overexpression of nt-delphosducin enhances the contractility of cardiomyocytes to the same extent as bARKct, suggesting that the effects of bARKct might be owing to inhibition of Gbg rather than to bAR resensitization.

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Section: Introductionmentioning

confidence: 99%

Effects of two Gβγ-binding proteins – N-terminally truncated phosducin and β-adrenergic receptor kinase C terminus (βARKct) – in heart failure

Li¹,

Laugwitz

Pinkernell

et al. 2003

Gene Ther

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“…This approach has been primarily done with the bARKct as a peptide inhibitor of GRK2. [42][43][44][45][46][47][48] A recent report has also shown similar effects with a small molecular inhibitor of GRK2 that, interestingly, appears to act as the bARKct in targeting G bg binding. 45 The bARKct was designed by us in the 1990s for targeted inhibition of the GRK2-Gbg interaction.…”

Section: Myocardial Grk2 As a Hf Gene Therapy Targetmentioning

confidence: 67%

“…43,49,50 In addition, viral delivery of bARKct (adenovirus and adeno-associated virus) has demonstrated successful inhibition of GRK2 activity connected with decreased bAR desensitization without disrupting normal signaling and leading to HF prevention or reversal in rats and rabbit models of HF. 40,44,45 Taking advantage of genetic HF models, Blaxall et al 48 demonstrated that the therapeutic bARKct effect is accompanied by normalization of cardiac gene expression. 48 Importantly, Williams et al 51 could demonstrate improved single myocyte contractility on isolated failing human cardiomyocytes following adenovirus-mediated gene transfer of bARKct.…”

Section: Myocardial Grk2 As a Hf Gene Therapy Targetmentioning

confidence: 99%

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

et al. 2012

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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.

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“…Electronic pacemakers are the most popular treatment for bradycardia, but biological alternatives, including implantation of cardiac pacemaking cells and genetic engineering of stem cells for implantation, may be far more effective alternatives [31,32]. One method used to generate pacemaking cells is to induce overexpression of the β-adrenergic receptor [31,[33][34][35][36]. Alternatively, delivering a voltage-gated channel protein, specifically the gene for hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, can induce cells to act as pacemakers [7,32,37].…”

Section: Pacemakingmentioning

confidence: 99%

“…Furthermore, a variety of cells can be used, including fibroblasts, cardiac cells and stem cells [31,[33][34][35][36]. Table 1 provides an overview of preclinical studies investigating gene-therapy based cardiac pacemaking.…”

Section: Pacemakingmentioning

confidence: 99%

Non‐viral gene therapy for myocardial engineering

Holladay

O’Brien

Pandit

2010

WIREs Nanomed Nanobiotechnol

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Despite significant advances in surgical and pharmacological techniques, myocardial infarction remains the main cause of morbidity in the developed world because no remedy has been found for the regeneration of infarcted myocardium. Once the blood supply to the area in question is interrupted, the inflammatory cascade, among other mechanisms, results in the damaged tissue becoming a scar. The goals of cardiac gene therapy are essentially to minimize damage, to promote regeneration or some combination thereof. While the vector is, in theory, less important than the gene being delivered, the choice of vector can have a significant impact. Viral therapies can have very high transfection efficiencies, but disadvantages include immunogenicity, retroviralmediated insertional mutagenesis and the expense and difficulty of manufacture. For these reasons, researchers have focused on non-viral gene therapy as an alternative. In this review, naked plasmid delivery, or the delivery of complexed plasmids, and cellmediated gene delivery to the myocardium will be reviewed. Pre-clinical and clinical trials in the cardiac tissue will form the core of the discussion. While unmodified stem cells are sometimes considered therapeutic vectors based on paracrine mechanisms of action basic understanding is limited. Thus, only genetically modified cells will be discussed as cell-mediated gene therapy.Ischemic heart disease, which includes acute damage due to myocardial infarction (MI) and chronic damage due to atherosclerotic narrowing of vessels, accounts for 35% of deaths reported in the United States every year [1]. MI, which is literally the death of cardiac tissue due to lack of 2 oxygen supply, is the result of the occlusion of a coronary artery. Within a few hours of interrupted blood supply, affected cardiomyocytes die. While the body has adaptive mechanisms, such as hypertrophy of the undamaged cardiac muscle and the development of collateral blood supply to minimize the damage, ischemic heart disease remains the most common cause of death in developed countries [2].The delivery of plasmid DNA to the myocardium is a complicated problem as the transfection efficiency of unmodified DNA is quite low, but complexation with agents designed to improve transfection can increase the cytotoxicity of the treatment [3]. Delivery of uncomplexed plasmid DNA is conceptually the simplest gene delivery technique, but these plasmids have extremely low transfection efficiencies in vitro and are not particularly effective in vivo. Compared to viral vectors, transgene expression is almost negligible and the expression time is also very limited [4]. However, there are significant advantages in using plasmids instead of viruses, such as ease of preparation (large and small scale), very low immunogenicity (as there are essentially no protein or membrane components in the plasmid), capacity for long term storage, ease of recombinant manipulation and much larger expression cassettes [4]. A variety of non-viral techniques are available to improve...

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In Vivo Ventricular Gene Delivery of a β-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction

Cited by 175 publications

References 19 publications

Effects of two Gβγ-binding proteins – N-terminally truncated phosducin and β-adrenergic receptor kinase C terminus (βARKct) – in heart failure

Effects of two Gβγ-binding proteins – N-terminally truncated phosducin and β-adrenergic receptor kinase C terminus (βARKct) – in heart failure

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

Non‐viral gene therapy for myocardial engineering

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