Heart failure remains one of the most highly prevalent and costly syndromes that leads to morbidity and mortality in the United States and increasingly around the world. ?1-adrenergic receptor (?1AR) signaling is critical to the regulation of cardiac function in response to sympathetic input but becomes deleterious in response to chronic catecholamine stimulation during the progression of heart failure. Recently, ?1AR- mediated transactivation of epidermal growth factor receptor (EGFR) was reported to relay cardioprotection under conditions of chronically elevated catecholamine stimulation, maintaining normal cardiac function and promoting cell survival via reduced apoptosis. The molecular mechanism(s) by which ?1AR-mediated EGFR transactivation relays cardioprotective signaling are poorly understood and the apoptotic pathways regulated by this process are unknown. Recent evidence showed that ?1AR and EGFR associate as a receptor complex in a G protein-coupled receptor kinase (GRK)-dependent manner, though the role of specific GRKs in the regulation of ?1AR-EGFR association is unknown. Further, differential ligand stimulation of the ?1AR-EGFR complex by catecholamine or EGF was shown to induce divergent receptor complex internalization and trafficking of downstream effectors. While proteomic studies of EGFR signaling have begun to describe protein networks, or signalosomes, assembled in response to EGF stimulation, the EGFR signalosome response to catecholamine-mediated stimulation of the ?1AR-EGFR complex has not been characterized. Since the molecular regulation of ?1AR-EGFR association and subsequent intracellular signaling may contribute to beneficial cardiac outcomes during heart failure, characterization of this novel signaling paradigm may lead to an improved therapeutic approach to heart failure. Thus, the aims of this proposal are to: 1) define the role of cardiac GRKs in the regulation of ?1AR-EGFR association, 2) determine how differential stimulation of the ?1AR-EGFR complex impacts receptor trafficking and signaling normally and during heart failure, and 3) characterize the impact of catecholamine stimulation of the ?1AR-EGFR complex on apoptotic signaling and regulation of the EGFR signalosome normally and during heart failure.
These aims will be assessed by elucidating the kinetics of ?1AR-EGFR association, trafficking and downstream signaling responses through the use of fluorescent resonance energy transfer (FRET), immunoprecipitation, radioligand binding, RT-PCR and mass spectroscopy. Regulation of ?1AR-EGFR association normally and during heart failure will be assessed using neonatal murine cardiomyocytes and whole heart preparations from wild-type and cardiac- specific GRK knockout mice with or without myocardial infarction. These studies will provide novel insight into how the ?1AR-EGFR complex exerts cardioprotection, identifying key signaling pathways for development of an improved molecular approach to heart failure therapy.
Relevance: Heart failure remains a leading cause of morbidity and mortality in the United States and increasingly abroad. By defining the molecular mechanisms that lead to preservation of cardiac function and increased survival during heart failure, new therapeutic strategies can be developed to augment beneficial cardiac signaling.
| Grisanti, Laurel A; Thomas, Toby P; Carter, Rhonda L et al. (2018) Pepducin-mediated cardioprotection via ?-arrestin-biased ?2-adrenergic receptor-specific signaling. Theranostics 8:4664-4678 |
| Kolpakov, Mikhail A; Tilley, Douglas G; Sabri, Abdelkarim (2017) G?q Signaling in the Regulation of Autophagy and Heart Failure. J Cardiovasc Pharmacol 69:212-214 |
| Guo, Shuchi; Carter, Rhonda L; Grisanti, Laurel A et al. (2017) Impact of paroxetine on proximal ?-adrenergic receptor signaling. Cell Signal 38:127-133 |
| Grisanti, Laurel A; Guo, Shuchi; Tilley, Douglas G (2017) Cardiac GPCR-Mediated EGFR Transactivation: Impact and Therapeutic Implications. J Cardiovasc Pharmacol 70:3-9 |
| Hooshdaran, Bahman; Kolpakov, Mikhail A; Guo, Xinji et al. (2017) Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury. Basic Res Cardiol 112:62 |
| Tilley, Douglas G; Sabri, Abdelkarim (2017) DUSPs as critical regulators of cardiac hypertrophy. Clin Sci (Lond) 131:155-158 |
| Grisanti, Laurel A; Traynham, Christopher J; Repas, Ashley A et al. (2016) ?2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. Proc Natl Acad Sci U S A 113:15126-15131 |
| Grisanti, Laurel A; Gumpert, Anna M; Traynham, Christopher J et al. (2016) Leukocyte-Expressed ?2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury. Circulation 134:153-67 |
| Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) ?-arrestin-biased signaling through the ?2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16 |
| Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang et al. (2016) BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes. J Mol Cell Cardiol 92:10-20 |
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