Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation

Latt S. Mansor; Maria da Luz Sousa Fialho; Georgina Yea; Will A. Coumans; James A. West; Matthew Kerr; Carolyn A. Carr; Joost J. F. P. Luiken; Jan F. C. Glatz; Rhys D. Evans; Julian L. Griffin; Damian J. Tyler; Kieran Clarke; Lisa C. Heather

doi:10.1093/cvr/cvx045

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation

Latt S. Mansor, Maria da Luz Sousa Fialho, Georgina Yea, Will A. Coumans, James A. West, Matthew Kerr, Carolyn A. Carr, Joost J. F. P. Luiken, Jan F. C. Glatz, Rhys D. Evans, Julian L. Griffin, Damian J. Tyler, Kieran Clarke, Lisa C. Heather^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Aims The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.

Methods and results Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxiareoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.

Conclusions Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.

Original language	English
Pages (from-to)	737-748
Number of pages	12
Journal	Cardiovascular Research
Volume	113
Issue number	7
DOIs	https://doi.org/10.1093/cvr/cvx045
Publication status	Published - 1 Jun 2017

Keywords

Metabolism
Energy
Fatty acid
Hypoxia
Glucose
CHAIN FATTY-ACIDS
MYOCARDIAL SUBSTRATE METABOLISM
MAGNETIC-RESONANCE
CARDIAC METABOLISM
PERFUSED HEARTS
DB/DB MICE
SHORT-TERM
RAT-HEART
INSULIN
CARDIOMYOPATHY

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Cite this

Mansor, L. S., Fialho, M. D. L. S., Yea, G., Coumans, W. A., West, J. A., Kerr, M., Carr, C. A., Luiken, J. J. F. P., Glatz, J. F. C., Evans, R. D., Griffin, J. L., Tyler, D. J., Clarke, K., & Heather, L. C. (2017). Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation. Cardiovascular Research, 113(7), 737-748. https://doi.org/10.1093/cvr/cvx045

@article{19d34c1adee54bababa1b1578aa30062,

title = "Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation",

abstract = "Aims The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.Methods and results Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxiareoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.Conclusions Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.",

keywords = "Metabolism, Energy, Fatty acid, Hypoxia, Glucose, CHAIN FATTY-ACIDS, MYOCARDIAL SUBSTRATE METABOLISM, MAGNETIC-RESONANCE, CARDIAC METABOLISM, PERFUSED HEARTS, DB/DB MICE, SHORT-TERM, RAT-HEART, INSULIN, CARDIOMYOPATHY",

author = "Mansor, {Latt S.} and Fialho, {Maria da Luz Sousa} and Georgina Yea and Coumans, {Will A.} and West, {James A.} and Matthew Kerr and Carr, {Carolyn A.} and Luiken, {Joost J. F. P.} and Glatz, {Jan F. C.} and Evans, {Rhys D.} and Griffin, {Julian L.} and Tyler, {Damian J.} and Kieran Clarke and Heather, {Lisa C.}",

year = "2017",

month = jun,

day = "1",

doi = "10.1093/cvr/cvx045",

language = "English",

volume = "113",

pages = "737--748",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "7",

}

Mansor, LS, Fialho, MDLS, Yea, G, Coumans, WA, West, JA, Kerr, M, Carr, CA, Luiken, JJFP, Glatz, JFC, Evans, RD, Griffin, JL, Tyler, DJ, Clarke, K & Heather, LC 2017, 'Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation', Cardiovascular Research, vol. 113, no. 7, pp. 737-748. https://doi.org/10.1093/cvr/cvx045

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation. / Mansor, Latt S.; Fialho, Maria da Luz Sousa; Yea, Georgina et al.
In: Cardiovascular Research, Vol. 113, No. 7, 01.06.2017, p. 737-748.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation

AU - Mansor, Latt S.

AU - Fialho, Maria da Luz Sousa

AU - Yea, Georgina

AU - Coumans, Will A.

AU - West, James A.

AU - Kerr, Matthew

AU - Carr, Carolyn A.

AU - Luiken, Joost J. F. P.

AU - Glatz, Jan F. C.

AU - Evans, Rhys D.

AU - Griffin, Julian L.

AU - Tyler, Damian J.

AU - Clarke, Kieran

AU - Heather, Lisa C.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Aims The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.Methods and results Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxiareoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.Conclusions Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.

AB - Aims The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.Methods and results Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxiareoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.Conclusions Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.

KW - Metabolism

KW - Energy

KW - Fatty acid

KW - Hypoxia

KW - Glucose

KW - CHAIN FATTY-ACIDS

KW - MYOCARDIAL SUBSTRATE METABOLISM

KW - MAGNETIC-RESONANCE

KW - CARDIAC METABOLISM

KW - PERFUSED HEARTS

KW - DB/DB MICE

KW - SHORT-TERM

KW - RAT-HEART

KW - INSULIN

KW - CARDIOMYOPATHY

U2 - 10.1093/cvr/cvx045

DO - 10.1093/cvr/cvx045

M3 - Article

C2 - 28419197

SN - 0008-6363

VL - 113

SP - 737

EP - 748

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 7

ER -