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

Award Number: R01HL160646
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Transendothelial transport and CD36 in the dysregulated lipid trafficking of failing hearts - 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 KO mice. Outcomes will provide unique information on molecular events modulating lipid content as new targets to resolve metabolic imbalances in failing hearts.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $620,403 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	4	11/8/2024	NON-COMPETING CONTINUATION	$620,403
														Subtotal = $620,403

Issue Date FY: 2024 ( Subtotal = $675,551 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	3	11/8/2023	NON-COMPETING CONTINUATION	$620,403
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	3	6/24/2024	NON-COMPETING CONTINUATION	$55,148
														Subtotal = $675,551

Issue Date FY: 2023 ( Subtotal = $690,649 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$69,065
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	11/22/2022	NON-COMPETING CONTINUATION	$621,584
														Subtotal = $690,649

Issue Date FY: 2022 ( Subtotal = $702,400 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	12/13/2021	NEW	$702,400
														Subtotal = $702,400

Grand Total All Awards = $2,689,003

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

Award Number: R01HL160646

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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