Small Molecule Disruption of G Signaling Inhibits the Progression of Heart Failure (original) (raw)
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Small Molecule Disruption of Gβγ Signaling Inhibits the Progression of Heart Failure
Circulation Research, 2010
Rationale: Excess signaling through cardiac G␥ subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein-coupled receptor kinase (GRK)2 to agonist-stimulated -adrenergic receptors (-ARs) in HF, leading to chronic -AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting G␥ signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule G␥ inhibition in HF. Methods and Results: We recently described novel small molecule G␥ inhibitors that selectively block G␥-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of G␥ and GRK2 in vitro and in HL60 cells. Here, we show they reduced -AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to -AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and -myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological G␥ signaling in the treatment of HF.
GRK2 as a novel gene therapy target in heart failure
Journal of Molecular and Cellular Cardiology, 2011
Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. HF is a chronic and progressive clinical syndrome characterized by a reduction in left ventricular (LV) ejection fraction and adverse remodeling of the myocardium. The past several years have seen remarkable progress using animal models in unravelling the cellular and molecular mechanisms underlying HF pathogenesis and progression. These studies have revealed potentially novel therapeutic targets/strategies. The application of cardiac gene transfer, which allows for the manipulation of targets in cardiomyocytes, appears to be a promising therapeutic tool in HF. β-adrenergic receptor (βAR) dysfunction represents a hallmark abnormality of chronic HF, and increased G protein-coupled receptor kinase 2 (GRK2) levels/activity in failing myocardium is among these alterations. In the past 15 years, several animal studies have shown that expression of a peptide inhibitor of GRK2 (βARKct) can improve the contractile function of failing myocardium including promoting reverse remodeling of the LV. Therefore, data support the use of the βARKct as a promising candidate for therapeutic application in human HF. Importantly, recent studies in cardiac-specific GRK2 knockout mice have corroborated GRK2 being pathological in failing myocytes. The purpose of this review is to discuss: 1) the alterations of βAR signalling that occur in HF, 2) the evidence from transgenic mouse studies investigating the impact of GRK2 manipulation in failing myocardium, 3) the therapeutic efficacy of in vivo βARKct gene therapy in HF, and 4) the intriguing possibility of lowering HF-related sympathetic nervous system hyperactivity by inhibiting GRK2 activity in the adrenal gland.
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.
Current and future G protein-coupled receptor signaling targets for heart failure therapy
Drug Design, Development and Therapy, 2013
Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of β-blockers and antagonists of the renin-angiotensin-aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the β-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.
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.
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.
Drug Development Research, 2019
The well‐known condition of heart failure is a clinical syndrome that results when the myocardium's ability to pump enough blood to meet the body's metabolic needs is impaired. Most of the cardiac activity is maintained by adrenoceptors, are categorized into two main α and β and three distinct subtypes of β receptor: β1‐, β2‐, and β3‐adrenoceptors. The β adrenoreceptor is the main regulatory macro proteins, predominantly available on heart and responsible for down regulatory cardiac signaling. Moreover, the pathological involvement of Angiotensin‐converting enzyme 1 (ACE1)/angiotensin II (Ang II)/angiotensin II type 1 (AT1) axis and beneficial ACE2/Ang (1‐7)/Mas receptor axis also shows protective role via Gi βγ, during heart failure these receptors get desensitized or internalized due to increase in the activity of G‐protein‐coupled receptor kinase 2 (GRK2) and GRK5, responsible for phosphorylation of G‐protein‐mediated down regulatory signaling. Here, we investigate the va...