Heart failure (HF) is a progressive disease affecting millions of people in the U.S. with the care of these patients costing billions of dollars annually While patient symptoms and mortality have been reduced with the use of neurohormone receptor antagonists, such as ?-blockers, their long-term impact on cardiac remodeling and patient lifespan is limited. G protein-coupled receptor (GPCR) signaling pathways have been shown for some time to be tunable, wherein protective pathways (often ?-arrestin-dependent) may be selected for through biased ligands, while deleterious pathways (usually G protein-dependent) are simultaneously inhibited. However, there has been a disappointing lack of progress in the development of biased ligands for ?- adrenergic receptors (?ARs) in particular, which have been shown to relay cardioprotective outcomes via ?- arrestin-dependent transactivation of epidermal growth factor receptor (EGFR). Over the last few years we have extensively characterized the subcellular signaling, transcriptional and cardiac remodeling responses that occur in response to both acute and chronic EGFR transactivation in cardiomyocytes and in whole heart following ?1AR stimulation. Our studies have highlighted the potential therapeutic benefit of ?1AR-mediated EGFR transactivation and provided rationale for its pursuit as a HF treatment strategy, however lack of specific tools has prevented the execution of definitive studies. In particular, bona fide ?1AR-specific ?arr/EGFR- biased ligands with enhanced efficacy, and that do not impact G protein-dependent signaling, do not exist. Thus, EGFR transactivation studies to date have relied upon EGFR inhibition in the presence of ?AR stimulation to indirectly measure its impact on cardiomyocyte/cardiac signaling, transcription and survival outcomes. Additionally, EGFR knockout animals are not viable, thereby preventing assessment of EGFR function in adult models of HF without the use of pharmacologic inhibitors that introduce selectivity and toxicity issues. With these issues in mind, we have begun to test pepducins, small peptide fragments of the intracellular loops of GPCRs that allosterically induce biased signaling, specifically for the ?1AR with the intent to drive EGR transactivation in the absence of G protein activation. These new molecular tools will allow positive characterization of ?1AR-mediated EGFR transactivation in cardiomyocytes for the first time, without the reliance upon pharmacological inhibitors. Additionally, we have generated a cardiomyocyte-specific inducible EGFR deletion mouse model that will definitively establish the impact of EGFR signaling in the heart in response to ?AR stimulation, as well as in the context of more broad forms of HF development. These studies will therefore provide the first direct assessment of the importance of cardiomyocyte-expressed EGFR during HF, as well as generate novel and potentially therapeutic agents with which to specifically engage ?1AR-depedent EGFR transactivation to promote survival signaling and reduce detrimental structural and functional outcomes during HF.

Public Health Relevance

Heart failure affects millions of patients and costs billions of dollars in treatment per year in the United States alone. Disease progression is mediated in large part by the release of neurohormones and subsequent activation of their receptor systems in the heart, including the beta adrenergic system. Through the development of new molecular tools to selectively enhance beta adrenergic receptor-mediated survival signaling through epidermal growth factor receptor activation, new therapeutic strategies can be developed to improve HF treatment. Further, understanding of the regulation of survival signaling by this pathway and the overall impact of epidermal growth factor receptor signaling in different forms of cardiac dysfunction will identify potential new therapeutic avenues to pursue in the treatment of HF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105414-07
Application #
9242051
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
Project Start
2010-12-15
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
7
Fiscal Year
2017
Total Cost
$390,000
Indirect Cost
$140,000
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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; 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
Wasilewski, Melissa A; Myers, Valerie D; Recchia, Fabio A et al. (2016) Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cell Signal 28:224-233

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