# Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $396,250

## Abstract

Summary
Acute ischemic injury, such as myocardial infarction (MI), is a major contributor toward the development of
heart failure (HF), a progressive disease affecting millions of patients and costing billions of dollars annually.
Leukocytes are rapidly recruited to the heart after ischemic injury where they regulate a wide variety of
responses including cardiomyocyte survival, fibrosis, infarct stabilization and revascularization. Initially,
inflammatory and phagocytic leukocytes are recruited to degrade dead cells and damaged matrix, followed by
reparative leukocytes to stabilize the myocardium and resolve the injury. As such, modulation of the balance
between leukocyte-dependent inflammation and resolution processes within the heart after ischemic injury is at
the forefront of recent efforts to diminish prolonged adverse post-ischemic remodeling and persistent
inflammation associated with chronic HF. The sympathetic nervous system can influence leukocyte
processes, in part via stimulation of β-adrenergic receptor (βAR) signaling, and becomes activated after
cardiac injury. We recently showed that, compared to normal mice, chimeric mice lacking β2AR expression in
cells of hematopoietic origin (β2ARKO BMT mice) displayed 100% mortality via cardiac rupture following MI,
which was associated with decreased leukocyte recruitment to the heart. Mechanistically, we have
demonstrated that β2AR acts in a signaling pathway-biased manner to regulate leukocyte responses to cardiac
injury via G protein coupled receptor kinase (GRK)/β-arrestin (βarr)-dependent β2AR signaling. Arising from
this work are questions related to the extent to which β2AR signaling regulates inflammatory versus reparative
leukocyte populations and their survival following cardiac injury, and whether biased β2AR signaling offers a
novel approach to regulate these processes to improve cardiac remodeling outcomes. Further, since β2AR
deletion negatively regulates leukocyte functions, the possibility exists that clinically used β-blockers may
similarly impact leukocyte responsiveness to ischemic injury and survival within the injured myocardium.
Therefore, we aim to 1) define the β2AR expression-dependent alterations in leukocyte survival following acute
cardiac injury, 2) evaluate the impact of β-blocker treatment on mouse and human leukocyte function and
survival, and 3) differentiate the effects of leukocyte-specific biased β2AR signaling on cardiac remodeling and
survival following injury. Overall, we will attain a fundamental understanding of the mechanisms and influence
of β2AR signaling on the early immune response to cardiac injury and determine whether β2AR-selective
therapeutics would offer fine-tuned strategies to regulate ischemic injury-induced remodeling and survival
outcomes.

## Key facts

- **NIH application ID:** 9838789
- **Project number:** 5R01HL139522-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Douglas Tilley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2017-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838789

## Citation

> US National Institutes of Health, RePORTER application 9838789, Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury (5R01HL139522-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838789. Licensed CC0.

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