# Cardiomyocyte selective modulation of natriuretic peptide signaling in cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $653,854

## Abstract

Project Summary:
In the last 30 years there has been a dramatic increase in our understanding of the genetic and non-genetic
mechanisms that contribute to the development of cardiomyopathy in humans. Despite this increased
mechanistic understanding, the risk of heart failure and sudden death remains high in this patient population.
While multiple small molecule agents reduce the morbidity and mortality of patients with cardiomyopathy, many
patients still progress to end stage disease. In addition, these small molecule agents act in a non-cell type
specific manner and their utilization is often limited by side effects. Likewise, pharmacological therapy to
prevent sudden death in individuals with cardiomyopathy remains lacking, and many patients still require an
implantable cardiac defibrillator (ICD). Therefore, new strategies are required to reduce disease progression
and sudden death in patients with cardiomyopathy. Preventing the degradation of circulating natriuretic
peptides by the chemical inhibition of neprilysin has proven to be very beneficial in patients with dilated
cardiomyopathy. The combination of the neprilysin inhibitor, sacubitril, and the angiotensin receptor blocker,
valsartan, not only reduced mortality secondary to heart failure but also significantly reduced sudden death in
the dilated cardiomyopathy population. However, in the landmark clinical trial PARADIGM-HF, many trial
participants developed symptomatic hypotension (14%), renal failure (3.3%), or hyperkalemia (16.1%) from
sacubitril/valsartan (LCZ696). In an effort to understand why alterations in NP signaling impact cardiomyopathy
remodeling and sudden death, we studied murine models deficient in either atrial natriuretic peptide (ANP) or
B-type natriuretic peptide (BNP). We found that reduced levels of either ANP or BNP led to increased stress
induced sudden death and ventricular arrhythmias. Mechanistically, we discovered that the phosphorylation of
the transcription factor CREB1 was regulated by NP signaling, and a reduction in CREB1 signaling sensitized
the heart to stress induced ventricular arrhythmias. We have now discovered that NP-PKG1 signaling can
activate protein inhibitor of activated STAT 1 (PIAS1), which regulates the levels of the key cardiomyocyte
calcium regulatory protein SERCA2a. We hypothesize that cardiomyocyte selective targeting of key natriuretic
peptide regulated pathways will improve myocardial function and reduce ventricular arrhythmia susceptibility in
cardiomyopathy while avoiding systemic side effects. Aim 1: Define how cardiomyocyte specific modulation of
PKG1 activity modifies cardiomyopathy progression and arrhythmia susceptibility. Aim 2: Determine the role of
PIAS1 in regulating cardiomyopathy progression and ventricular arrhythmias. Aim 3: Define how CREB1
signaling modifies cardiomyopathy remodeling and ventricular arrhythmias. At the conclusion of these high
impact studies, we will have defined how cardiomyocyte selective modulati...

## Key facts

- **NIH application ID:** 10980673
- **Project number:** 1R01HL169784-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Becker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $653,854
- **Award type:** 1
- **Project period:** 2024-07-09 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980673

## Citation

> US National Institutes of Health, RePORTER application 10980673, Cardiomyocyte selective modulation of natriuretic peptide signaling in cardiomyopathy (1R01HL169784-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10980673. Licensed CC0.

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