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Cardiomyocyte selective modulation of natriuretic peptide signaling in cardiomyopathy

Award Number: R01HL169784
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Cardiomyocyte selective modulation of natriuretic peptide signaling in cardiomyopathy - 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 modulation of natriuretic peptide signaling pathways modifies cardiac remodeling and arrhythmogenesis in preclinical cardiomyopathy models, setting the stage for future therapeutic strategies in humans.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $653,854 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	2	7/14/2025	NON-COMPETING CONTINUATION	$653,854
														Subtotal = $653,854

Issue Date FY: 2024 ( Subtotal = $653,854 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	7/9/2024	NEW	$653,854
														Subtotal = $653,854

Grand Total All Awards = $1,307,708

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Cardiomyocyte selective modulation of natriuretic peptide signaling in cardiomyopathy

Award Number: R01HL169784

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/09/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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