GRK2 as a novel gene therapy target in heart failure (original) (raw)
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Therapeutic potential of G-protein coupled receptor kinases in the heart
Expert Opinion on Investigational Drugs, 1999
The actions of G-protein coupled receptor kinases (GRKs) critically regulate β-adrenergic receptor (βAR) signalling. In the cardiovascular system, the βAR signalling pathway controls important responses of the heart such as the ability to contract (inotropy), the ability to contract faster (chronotropy) and the ability to relax (lusotropy). The observation that the βAR kinase (βARK1, also known as GRK2), the most abundant GRK in the heart, is increased in cardiovascular disease associated with impaired cardiac function, suggests that this molecule could have pathophysiological relevance in the setting of heart failure. Technological advances in the genetic engineering of mice have provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart. Recent studies have demonstrated that βARK1 plays a key role in not only the regulation of myocardial signalling, but also in cardiac function and development. Importantly, targeting the activity of GRKs, and βARK1 in particular, appears to represent a novel therapeutic strategy for the treatment of the failing heart. At present, gene therapy modalities are being tested which inhibit the activity of βARK1 in the heart. This technology makes it possible to test directly whether βARK1 inhibition in the setting of heart disease will improve the function of the compromised heart. Thus, these genetic approaches or the development of small molecule inhibitors of GRK activity, may lead to novel therapeutic approaches for cardiovascular disease.
Transgenic Mice Targeting the Heart Unveil G Protein-Coupled Receptor Kinases as Therapeutic Targets
ASSAY and Drug Development Technologies, 2003
GRKs critically regulate bAR signaling via receptor phosphorylation and the triggering of desensitization. In the heart, bARs control the chronotropic, lusitropic, and inotropic responses to the catecholamine neurotransmitters, norepinephrine and epinephrine. Signaling through cardiac bARs is significantly impaired in many cardiovascular disorders, including congestive heart failure. bARK1 (also known as GRK2) is the most abundant GRK in the heart, and it is increased in several cardiovascular diseases associated with impaired cardiac signaling and function, suggesting that this molecule could have pathophysiological relevance in the setting of heart failure. The ability to manipulate the mouse genome has provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart. Recent studies in several different mouse models have demonstrated that bARK1 plays a key role not only in the regulation of myocardial signaling, but also in cardiac function and development. Moreover, studies have shown that targeting the activity of GRKs, especially bARK1, appears to be a novel therapeutic strategy for the treatment of the failing heart. Gene therapy technology makes it possible, beyond what is possible in the mouse, to directly test in larger animals whether bARK1 inhibition in the setting of disease will improve the function of the compromised heart, and this methodology has also lead to compelling results. These genetic approaches or the development of small molecule inhibitors of bARK1 and GRK activity may advance therapeutic options for heart disease.
Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs
American Journal of Physiology-Heart and Circulatory Physiology, 1998
Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled receptor kinase 3 (GRK3) to explore the in vivo role of this GRK in cardiac function. GRK3 is expressed in the heart along with the β-adrenergic receptor kinase (β-ARK1) and GRK5. We have previously demonstrated that myocardial-targeted overexpression in transgenic mice of β-ARK1 (Koch, W.J., H. A. Rockman, P. Samama, R. A. Hamilton, R. A. Bond, C. A. Milano, and R. J. Lefkowitz. Science 268: 1350–1353, 1995) or GRK5 (Rockman, H.A., D.-J. Choi, N. U. Rahman, S. A. Akhter, R. J. Lefkowitz, and W. J. Koch. Proc. Natl. Acad. Sci. USA 93: 9954–9959, 1996) results in significant attenuation of β-adrenergic signaling and in vivo cardiac function and selective desensitization of angiotensin (ANG) II-mediated cardiac responses. Surprisingly, myocardial overexpression of GRK3 resulted in normal biochemical signaling through β-adrenergic receptors (β-ARs), and in vivo hemodynamic function in response ...
Myocardial G Protein-Coupled Receptor Kinases: Implications for Heart Failure Therapy
Proceedings of the Association of American Physicians, 1999
The 13-adrenergic signaling cascade is an important regulator of myocardial function. Significant alterations of this pathway are associated with several cardiovascular diseases, including congestive heart failure (CHF). Included in these alterations is increased activity and expression of G protein-coupled receptor kinases (GRKs), such as the 13-adrenergic receptor kinase (I3ARK I), which phosphorylate and desensitize 13-adrenergic receptors (I3ARs). A body of evidence is accumulating that suggests that GRKs, in particular I3ARK I, are critical determinants of cardiac function under normal conditions and in disease states. Transgenic mice with myocardialtargeted alterations of GRK activity have shown profound changes in the in vivo functional performance of the heart. Included in these studies is the compelling finding that inhibition of I3ARKI activity or expression significantly enhances cardiac function and potentiates I3AR signaling in failing cardiomyocytes. This article summarizes the advances made in the study of I3ARK I in the heart and addresses its potential as a novel therapeutic target for CHF.
Circulation, 1998
Background —Impaired myocardial β-adrenergic receptor (βAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial β-adrenergic receptor kinase (βARK1) activity because levels of this βAR-desensitizing G protein–coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for βAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize βARs to study the dynamic relationship between βAR activation and myocardial levels of βARK1. Methods and Results —Long-term in vivo stimulation of βARs results in the impairment of cardiac βAR signaling and increases the level of expression (mRNA and protein) and activity of βARK1 but not that of GRK5, a second ...
GRK2-Mediated Inhibition of Adrenergic and Dopaminergic Signaling in Right Ventricular Hypertrophy
Circulation, 2012
Background— The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein–coupled receptor kinase-2 (GRK2)–mediated uncoupling of β-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ–GRK2 interaction, using gallein, were tested. Methods and Results— Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding–induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular–Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac o...
Cell Communication and Signaling, 2013
Backgroundβ1- and β2–adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF).ResultsWe crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in e...
Circulation Research, 2012
H eart failure (HF), a leading cause of death in the Western world, often occurs as an end phase of pathological myocardial hypertrophy. 1 Hypertrophy is initially an adaptive response to stresses ranging from hypertension, valve disease, or cardiac injury. 2,3 In an attempt to normalize wall stress, cardiomyocytes enlarge, sarcomeres reorganize, fibroblasts proliferate, and hypertrophic genes, including the so-called fetal gene program, are upregulated. If prolonged, these responses lead to chamber dilation, myocardial apoptosis, and HF. 2,3 In pathological cardiac growth, the molecular pathways affecting transcription lie downstream of the nodal hypertrophic signal transducer, Gq. 1 Among these complex pathways are the class II histone deacetylases (HDACs). Physiologically opposed to cardiac growth, the HDACs repress expression of key hypertrophic genes, primarily through inhibition of myocyte enhancer factor 2 (MEF2). 3 Genetic deletion of the class II HDAC, HDAC5, sensitizes mice to cardiac stress, whereas murine deletion of MEF2 confers cardioprotection, decreasing pathological hypertrophy and attenuating upregulation of the fetal gene program. 4 HDAC kinases control nuclear HDAC activity as phosphorylation of HDAC5 induces its nuclear export and MEF2 derepression. [3] In This Issue, see p 947