# Molecular Basis of Postischemic Maladaptation in the Insulin Resistant Heart

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $387,500

## Abstract

ABSTRACT
Type 2 diabetes has reached epidemic proportions and is a leading cause of coronary heart disease in the
United States. Insulin resistance, a hallmark of type 2 diabetes, is associated with a 2 to 4 times higher risk of
cardiac morbidity and mortality following acute myocardial infarction (MI). The goals of this project are to
elucidate the molecular mechanisms linking insulin resistance to poor cardiac recovery after MI and to apply
this knowledge to develop therapeutic strategies for improving recovery of cardiac function in diabetic patients
at reperfusion. Uncoupling protein 3 (UCP3) is a mitochondrial anion carrier protein with antioxidant properties
involved in the metabolism of long-chain fatty acids (LCFA). Muscle UCP3 content is 50% lower in type 2
diabetic patients compared with healthy control subjects. A similar decrease is observed in the heart of mice
and rats with insulin resistance and type 2 diabetes. Using CRISPR/Cas9-targeted mutation in rats, we have
gathered preliminary data showing that a 50% decrease in cardiac UCP3 levels is sufficient to significantly
impair contractile recovery following ischemia. Our results further suggest that decreased functional recovery
of insulin resistant and UCP3 deficient hearts after ischemia is caused by a limited capacity to oxidize LCFA at
reperfusion, a defect that can be rescued by supplying medium-chain fatty acids (MCFA) as an alternative fuel.
Besides the bioenergetic deficit, impaired LCFA oxidation is known to cause a toxic accumulation of long-chain
ceramides and to increase oxidative stress. Therefore, we hypothesize that decreased UCP3 impairs the
recovery of systolic function in insulin resistant hearts following MI by limiting myocardial LCFA
oxidation, increasing mitochondrial dysfunction, and increasing cardiac myocyte death at reperfusion.
Three aims will address this hypothesis in mouse and rat models of dietary, pharmacologically, or genetically
induced myocardial insulin resistance or UCP3 deficiency (40-50% decrease) in a multisystem approach
combining in vivo models of MI/reperfusion to isolated beating hearts to isolated mitochondria. Aim 1 will
examine the effect of UCP3 deficiency and of its reversal on cardiac structural and functional recovery post
MI/reperfusion. Aim 2 will investigate the molecular consequences of UCP3 deficiency for mitochondrial
function and cardiac oxidative metabolism during ischemia/reperfusion. Aim 3 will test whether a metabolic
intervention based on increasing supply of MCFA to the heart can reverse these abnormalities. We expect this
project to reveal a novel molecular mechanism responsible for the poor prognosis of type 2 diabetic patients
following MI/reperfusion, and that it will provide the basis for additional studies to test MCFA-based treatments
as a metabolic strategy to improve cardiac outcomes in T2DM patients undergoing reperfusion after MI.

## Key facts

- **NIH application ID:** 9899301
- **Project number:** 5R01HL136438-03
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Romain Harmancey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899301

## Citation

> US National Institutes of Health, RePORTER application 9899301, Molecular Basis of Postischemic Maladaptation in the Insulin Resistant Heart (5R01HL136438-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899301. Licensed CC0.

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