# Transendothelial transport and CD36 in the dysregulated lipid trafficking of failing hearts

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $675,551

## Abstract

Project Summary:
The proposed research explores mechanisms of dysregulated lipid metabolism in failing hearts within the
dynamic processes of long chain fatty acid (LCFA) delivery from the circulation to metabolism in the
cardiomyocyte (CM). We will explore the roles of LCFA delivery by endothelial cells (EC) to CMs and rates of
LCFA uptake by CMs in adverse metabolic remodeling in a mouse model of heart failure that recapitulates key
metabolic defects in failing human hearts. Hearts rely on LCFA oxidation, up to 70% of fuels, to meet ATP
demand. LCFA are also esterified into the neutral triglyceride (TG) pool and into physiologically active acyl-
derivatives. In failing hearts, LCFA oxidation is reduced and the lipid profile becomes toxic. We have shown a
reduction in the central LCFA metabolite, acyl-CoA, in failing hearts is detrimental, and increased acyl
CoA production by ACSL1 improves metabolic state and mitigates functional decline. 13C NMR of hearts
revealed an exponential component of 13C LCFA entry into TG that reflects LCFA uptake rate and is sensitive
to activity of the LCFA transporter, CD36. LCFA uptake is also accelerated by metabolic trapping via
esterification of LCFA to acyl-CoA by ACSL1, a process that is sex-dependent. Experiments on mice with cell-
specific, CD36 deletion in ECs (EC-CD36 KO) and CMs (CM-CD36 KO) will support the objective to study the
separate roles of LCFA delivery by ECs to CMs and uptake by CMs on LCFA metabolism within competing
pathways, including deleterious ceramide formation in failing hearts. Potential differences in LCFA uptake and
metabolism between two primary physiological sources, albumin-bound LCFA and lipoprotein-bound TG, will
be studied. The hypothesis is: a) the contributions of EC CD36-dependent and independent transendothelial
transport of LCFAs into CMs of normal and diseased hearts determine the metabolic fate of LCFAs, separate
from CM CD36 activity, and depend on the LCFA source; b) there are sex-dependent differences in both CD36
transport of LCFA and trapping of LCFAs into CMs via esterification that contribute to the lipotoxic profile of
failing hearts. Specific aims are: 1. Elucidate EC CD36 contributions to transendothelial transport of LCFA
uptake kinetics and metabolic fate in normal and failing hearts of male vs. female EC-CD36 KO mice. 2.
Distinguish CM-CD36 from EC contributions to LCFA uptake kinetics and metabolic fate in hearts of normal
and failing heats of male vs. female CM-CD36 KO mice. 3. Elucidate reciprocal effects of CD36 transport and
metabolic trapping by ACSL1 on LCFA use in normal and failing hearts, by silencing of CD36 in hearts having
low overexpression of ACSL1 (MHC-ACSL1 J3) and in hearts from crossed, MHC-ASCL1xEC-CD36 KO and
MHC-ASCL1xCM-CD36 KO mice. 4. Distinguish contributions of EC-CD36 and CM-CD36 to LCFA uptake
rates and metabolism from albumin-bound vs. chylomicron-bound sources in normal and failing hearts of wild
type, EC-CD36 KO, and CM-CD36 ...

## Key facts

- **NIH application ID:** 10745336
- **Project number:** 5R01HL160646-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** E DOUGLAS LEWANDOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $675,551
- **Award type:** 5
- **Project period:** 2021-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745336

## Citation

> US National Institutes of Health, RePORTER application 10745336, Transendothelial transport and CD36 in the dysregulated lipid trafficking of failing hearts (5R01HL160646-03). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/10745336. Licensed CC0.

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