# Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2022 · $491,209

## Abstract

Pathological stresses, such as pressure overload in the left ventricles of patients with hypertension and aortic
valve stenosis, cause cardiac hypertrophy, a major risk factor of congestive heart failure. Hypertrophic and
failing hearts shift substrate utilization preference from fatty acids to glucose, ketone bodies, and others.
However, the interplay between the energetic state and the mitochondrial/metabolic remodeling in the
hypertrophic and failing remains incompletely understood. Most of the past studies are based on models with
confounding conditions. F1Fo-ATP synthase is an essential enzyme complex that generates ATP in
mitochondria, thus playing a central role in cellular energetics. Genetic defects of F1Fo-ATP synthase are rare
but deadly because of dilated cardiomyopathy and neuromuscular disorders. How those patients with partial
F1Fo-ATP synthase deficiencies respond to pathological stresses is unclear. It is documented that F1Fo-ATP
synthase is impaired in pathological hearts from patients and animals. Our recent study revealed that
enhancing F1Fo-ATP synthase structure/function using gene therapy restored cardiac function in the
hypertrophied hearts, corroborating the concept of targeting F1Fo-ATP synthase as a novel protective therapy
for heart failure. Our prior studies demonstrated that mice lacking F1Fo-ATP synthase assembly factors, such
as ATPAF1, lead to F1Fo-ATP synthase deficiencies with cardiomyopathy. Therefore, our central hypothesis is
that enhancing F1Fo-ATP synthase capacity to facilitate ATP production efficiency will mitigate
mitochondrial disorders and the ensued cardiac hypertrophy and failure. We propose to test the central
hypothesis with two aims. In aim 1, we will test that the F1Fo-ATP synthase deficiency is an amendable
pathogenic factor in heart failure progression. Experiments will provide evidence to support that partial F1Fo-
ATP synthase deficiency contributes to the pathological progression of heart failure, and gene therapies
correcting the deficiency will slow the heart failure progression. In aim 2, we will define how F1Fo-ATP
synthase capacities directly correlate to mitochondrial homeostasis and metabolic remodeling in
cardiomyocytes of the adult heart. Therefore, this proposed project will provide definitive evidence to support
innovative gene therapy and define the underpinning mechanisms. The proposed study will yield novel insights
into the primary mechanisms underlying metabolic remodeling in cardiac pathological hypertrophy progression.
The preclinical animal study will lay the groundwork for innovative gene therapies, which will significantly
impact patient care.

## Key facts

- **NIH application ID:** 10522598
- **Project number:** 1R01HL160969-01A1
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** QINGLIN YANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $491,209
- **Award type:** 1
- **Project period:** 2022-09-14 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522598

## Citation

> US National Institutes of Health, RePORTER application 10522598, Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure (1R01HL160969-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522598. Licensed CC0.

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