# Novel downstream effectors of protein kinase G in hypertensive disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $622,215

## Abstract

Abstract
Hypertension is an enormous health and socio-economic burden in the United States and is a leading cause of
cardiovascular morbidity and mortality worldwide. Overall, 1 in 3 of Americans have hypertension, and nearly 2
in 3 of Americans over the age of 65 years. Hypertension significantly increases the risk of developing heart
failure (HF), whereas reducing blood pressure decreases the risk. It is known that hypertension is the most
common risk factor in the development of HF with preserved ejection fraction (HFpEF) by a mechanism where
systemic inflammation and activation of reactive oxygen species reduces nitric oxide bioavailability and impairs
Protein kinase G (PKG) signaling. Chronic hypertension is characterized by impaired systolic and diastolic
cardiac function and pathological remodeling, and excessive renal sodium retention and volume overload, which
together contribute to progression to HFpEF and a poor prognosis. Therapies attempting to reduce blood
pressure in HFpEF patients have mostly failed to yield positive results. Many patients have hypertension that is
resistant to conventional therapy, and because the majority of HFpEF patients are elderly, they display aging
inherent deficits in nitric oxide bioavailability and PKG signaling that make available therapies less effective.
Although, it is known that impaired PKG signaling is central to the cardio-renal deficits related to hypertension
especially in older individuals, therapies specifically designed to enhance PKG activity have not been successful.
Our preliminary studies have explored an alternative approach to manipulating PKG levels to improve outcomes
in hypertension and HFpEF by bypassing complex signaling cascades in favor of directly targeting the
downstream effectors of PKG. We have identified a phosphorylatable serine residue 273 (S273) in the regulatory
protein MyBPC as a critical specific downstream target of PKG that is upregulated in various models of pressure
overload-induced hypertension, but is downregulated in models of HFpEF. These observations lay the
foundation for our general hypothesis that increasing S273 phosphorylation levels in chronic Htn prevents
progression to HFpEF. In Aim 1 we will define the PKG-specific in vitro molecular mechanisms of S273
phosphorylation, in Aim 2 we will utilize experimental models of hypertension and HFpEF and novel transgenic
animal models to determine the in vivo functional consequences of altered PKG levels and aging, and in Aim 3
we will utilize in vivo cardioselective AAV9 viral gene delivery of phosphomimetic S273 to prevent or reverse the
HFpEF phenotype in aged mice and in mice with ablated PKG. Successful completion of these mechanistic
studies have the promise to identify S273 as a novel therapeutic strategy to treat hypertension-induced HFpEF,
a devastating disease with no effective treatments.

## Key facts

- **NIH application ID:** 10380140
- **Project number:** 5R01HL153236-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Julian Stelzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $622,215
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380140

## Citation

> US National Institutes of Health, RePORTER application 10380140, Novel downstream effectors of protein kinase G in hypertensive disease (5R01HL153236-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10380140. Licensed CC0.

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