# Roles for SGK1 in Cardiometabolic Heart Failure with Preserved Ejection Fraction

> **NIH NIH R56** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $732,779

## Abstract

Project Summary:
Heart failure with preserved ejection fraction (HFpEF) has emerged as the greatest unmet medical need in
cardiovascular medicine, comprising 50% of all HF cases, with a US prevalence of ³3 million. HFpEF is
associated with high morbidity and mortality, with a 5-year survival after hospitalization worse than most cancers
of ~35% and, unlike the better understood heart failure with reduced ejected fraction (HFrEF), there are no
evidence-based therapies for HFpEF. HFpEF represents an entirely new disease threat because of the systemic
metabolic and endocrine nature of its pathogenesis. And, while HFpEF is heterogeneous in its clinical
presentation, arguably the most prevalent form is cardiometabolic HFpEF (cMet HFpEF), where the main
comorbidities are obesity, type 2 diabetes, and hypertension. These same comorbidities are the major drivers of
concomitant obesity-related diseases that includes nonalcoholic fatty liver disease (NAFLD), which is prevalent
in more than 50% of HFpEF patients and has been demonstrated to be an independent predictor of all-cause
mortality in HFpEF. This is of unique concern as the obesity epidemic continues to grow with current estimations
that 45% of the world’s population is either overweight or obese. Our preliminary data support the notion that the
heart is a primary regulator of global metabolic syndrome through the serine-threonine kinase, serum
glucocorticoid kinase 1 (SGK1). Global SGK1 overexpression has been demonstrated to promote increased
obesity, dyslipidemia, while liver-specific deletion of SGK1 has been shown to protect against NAFLD. While
there is a clear connection between SGK1 and obesity-related metabolic syndrome, neither a role for SGK1 in
cMet HFpEF nor the mechanism by which SGK1 regulates cellular metabolism have been investigated. In this
proposal, we will focus on cardiac-specific SGK1 in cMet HFpEF with the hypothesis that SGK1 promotes cardiac
pathology and subsequent global metabolic dysfunction in cMet HFpEF via regulating mTORC1 activity and
cardiac metabolism. We will address this hypothesis using cardiac-specific targeting of SGK1 in a mouse model
of cMet HFpEF with a focus on assessments of cardiac function and metabolism, as well as mechanistic studies
in primary cardiomyocytes, in the following Specific Aims which are to: (Aim 1) determine the role for cardiac
SGK1 in regulating heart function, metabolism, and heart directed inter-organ communication during cMet
HFpEF, (Aim 2) determine whether PRAS40 inhibition by SGK1 promotes mTORC1 mediated pathologic cardiac
metabolic inflexibility during cMet HFpEF, and (Aim 3) evaluate the therapeutic efficacy of a novel SGK1 inhibitory
peptide for preserving cardiac function and systemic metabolism during cMet HFpEF. These studies are
significant as the present the opportunity to identify novel secreted factors from the heart that regulate global
metabolic health as well as to test new therapeutic targets for both HFpEF and o...

## Key facts

- **NIH application ID:** 11227474
- **Project number:** 7R56HL174545-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Erik Blackwood
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $732,779
- **Award type:** 7
- **Project period:** 2024-09-26 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11227474

## Citation

> US National Institutes of Health, RePORTER application 11227474, Roles for SGK1 in Cardiometabolic Heart Failure with Preserved Ejection Fraction (7R56HL174545-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11227474. Licensed CC0.

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