# Role of S-Nitrosylation on Beta-Adrenergic Signaling in Cardiac Injury and Repair

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $702,607

## Abstract

SUMMARY:
During the development of heart failure (HF), especially after ischemic injury, derangements in myocardial β-
adrenergic receptor (βAR) signaling contribute centrally to pathogenesis, including signal uncoupling and
receptor desensitization leading to myocyte death and contractility defects. Waning of signaling through cardiac
βARs and other G protein-coupled receptors (GPCRs) is classically regulated via receptor phosphorylation and
internalization mediated by GPCR kinases (GRKs) and β-arrestins (β-Arrs). This is significant since the activity
of GRK2, which is elevated in myocardium after injury/stress, is pathologic in HF and its inhibition is therapeutic.
Through a long-standing collaboration, the Koch and Stamler laboratories have found that GPCRs are regulated
by nitric oxide (NO), through S-nitrosylation of cysteine to form protein S-nitrosothiol (SNO), including profound
regulation of GRK2 and of β-Arr2. Since cardiac GPCRs, including all three βARs, can activate NO synthase
(NOS) enzymes, there is a need to discover how this can promote SNO-mediated cardioprotection, especially
downstream of β2- and β3ARs. Our prior work has shown that NO from endothelial NOS (eNOS) inhibits GRK2
by S-nitrosylation at Cys340. Loss of SNO-based regulation in GRK2-C340S mutant knock-in (KI) mice leads to
un-checked and enhanced GRK2 activity, and to increased ischemic injury, and to dysfunction during aging. Our
labs have also shown that neuronal/inducible NOS (n/iNOS) activity can regulate β-Arr2 through SNO-Cys253
to maintain physiological βAR signaling in the heart. The loss of this SNO-β-Arr2 regulation in β-Arr2-C253S KI
mice leads to increased βAR desensitization and HF. Additionally, the Stamler lab recently discovered that β2AR
is S-nitrosylated at Cys265 and that this modification regulates β2AR desensitization. Together these data
suggest tightly integrated regulation of βAR/GPCR function via receptor-stimulated S-nitrosylation, which plays
a central but largely unappreciated role in controlling myocardial function. Our data provides novel insight into
consequences of the nitroso-redox imbalance in failing heart. The Central Hypothesis of this Multi-PI proposal
is that cardiac βAR signaling and desensitization via GRK2 and β-Arr2 are regulated by S-nitrosylation and that
nitroso-redox stress can be understood in terms of altered SNO of receptor, GRK and β-Arr to significantly impair
the heart’s response to injury. Specific Aims are: [1] To determine whether GRK2 inhibition via S-nitrosylation
plays a mechanistic role in selective βAR responses during cardiac ischemic injury; [2] To determine if β2AR is
S-nitrosylated in the ischemic heart and whether this impacts injury and repair; [3] To determine if regulation of
β-Arr2 by S-nitrosylation tunes βAR responses during cardiac dysfunction after injury and is integrated with β2AR
and GRK2 SNO regulation. Successful completion of these studies will illuminate the role of S-nitrosylation in
t...

## Key facts

- **NIH application ID:** 10370376
- **Project number:** 5R01HL157151-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Walter J. Koch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $702,607
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370376

## Citation

> US National Institutes of Health, RePORTER application 10370376, Role of S-Nitrosylation on Beta-Adrenergic Signaling in Cardiac Injury and Repair (5R01HL157151-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10370376. Licensed CC0.

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