# Characterization of beta-arrestin-biased beta 2-adrenergic receptor signaling in cardiovascular function

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $611,217

## Abstract

G protein-coupled receptors (GPCRs) are essential mediators of neurohormonal signaling in both the
normal and failing heart. β-adrenergic receptors (βARs) in particular control many facets of cardiomyocyte
function, including contractility and survival signaling, through the activation of both G protein-dependent and
β-arrestin-dependent signaling pathways. β-blockers are commonly used in the treatment of heart failure and
act to block cardiomyocyte cell death. While G protein-dependent βAR signaling enhances cardiomyocyte
death during heart failure, β-arrestin-biased βAR signaling has been suggested to promote cardiomyocyte
survival in the heart following acute cardiac injury or during heart failure. Although the clinically used β-blocker
carvedilol has been shown to induce β-arrestin-biased βAR signaling in model cells, we have found that
carvedilol actually ablates cardiomyocyte contraction. Thus, we believe β-arrestin-biased βAR modulators that
promote survival, but not at the expense of cardiomyocyte contractility, would serve as more effective
therapeutic agents for heart failure.
 Our recent work has detailed the development of pepducins, palmitoylated peptides from the intracellular
loops of a GPCR that selectively confer biased signaling via either G protein- or arrestin-dependent pathways.
In particular, several pepducins designed from the first intracellular loop of the β2AR were discovered to be
completely β-arrestin-biased. Further, we have shown for the first time that the most potent of these
compounds, ICL1-9, enhances cardiomyocyte contraction in a β2AR- and β-arrestin-dependent manner. This is
the first demonstration of a β-arrestin-biased β2AR modulator enhancing cardiomyocyte contractility in the
absence of G protein activation, an exciting finding that has the potential to greatly improve heart failure
therapeutics. We hypothesize that compounds that promote β-arrestin-biased β2AR signaling will be useful in
the treatment of heart failure and propose to identify and further characterize the ability of such compounds to
improve cardiac function. To test this hypothesis we will: 1) Dissect the mechanism of β-arrestin-biased β2AR
signaling using ICL1-9 as a model; 2) Perform high throughput screening and characterization of compounds
that promote β-arrestin-biased β2AR signaling and define their target and mechanism of action; 3) Determine
the mechanism of β-arrestin-biased β2AR-mediated cardiomyocyte contractility and its impact on cardiac
function in vivo; and 4) Evaluate the effects of β-arrestin-biased β2AR signaling on cardiomyocyte survival in
vitro and in response to acute cardiac injury in vivo. Overall, the goal of this project is to understand the
mechanism of β-arrestin-biased β2AR signaling and its impact on cardiomyocyte survival and function with a
long-term goal of developing novel therapeutics for the treatment of heart failure.

## Key facts

- **NIH application ID:** 9844963
- **Project number:** 5R01HL136219-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Jeffrey L Benovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $611,217
- **Award type:** 5
- **Project period:** 2017-01-09 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844963

## Citation

> US National Institutes of Health, RePORTER application 9844963, Characterization of beta-arrestin-biased beta 2-adrenergic receptor signaling in cardiovascular function (5R01HL136219-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844963. Licensed CC0.

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