Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery

Jeevan Nagendran; Thomas Pulinilkunnil; Petra C. Kienesberger; Miranda M. Sung; David Fung; Maria Febbraio; Jason R.B. Dyck

doi:10.1016/j.yjmcc.2013.07.020

Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery

Jeevan Nagendran, Thomas Pulinilkunnil, Petra C. Kienesberger, Miranda M. Sung, David Fung, Maria Febbraio, Jason R.B. Dyck

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Resumen

Although pre-clinical evidence has suggested that partial inhibition of myocardial fatty acid oxidation (FAO) and subsequent switch to greater glucose oxidation for ATP production can prevent ischemia/reperfusion injury, controversy about this approach persists. For example, mice with germline deletion of the FA transporter CD36, exhibited either impaired or unchanged post-ischemic functional recovery despite a 40-60% reduction in FAO rates. Because there are limitations to cardiac studies utilizing whole body CD36 knockout (total. CD36KO) mice, we have now generated an inducible and cardiomyocyte-specific CD36 KO (ic. CD36KO) mouse to better address the role of cardiomyocyte CD36 and its regulation of FAO and post-ischemic functional recovery. Four to six weeks following CD36 ablation, hearts from ic. CD36KO mice had significantly decreased FA uptake compared to controls, which was paralleled by significant reductions in intramyocardial triacylglycerol content. Analysis of cardiac energy metabolism using ex vivo working heart perfusions showed that reduced FAO rates were compensated by enhanced glucose oxidation in the hearts from ic. CD36KO mice. In contrast to the total. CD36KO mice, hearts from ic. CD36KO mice exhibited significantly improved functional recovery following ischemia/reperfusion (18. min of global no-flow ischemia followed by 40. min of aerobic reperfusion). This improved recovery was associated with lower calculated proton production prior to and following ischemia compared to controls. Moreover, the amount of ATP generated relative to cardiac work was significantly lower in the hearts from ic. CD36KO mice compared to controls, indicating significantly increased cardiac efficiency in the hearts from ic. CD36KO mice. These data provide genetic evidence that reduced FAO as a result of diminished CD36-mediated FA uptake improves post-ischemic cardiac efficiency and functional recovery. As such, targeting cardiomyocyte FA uptake and FAO via inhibition of CD36 in the adult myocardium may provide therapeutic benefit during ischemia-reperfusion.

Idioma original	English
Páginas (desde-hasta)	180-188
Número de páginas	9
Publicación	Journal of Molecular and Cellular Cardiology
Volumen	63
DOI	https://doi.org/10.1016/j.yjmcc.2013.07.020
Estado	Published - oct. 2013
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
This work was supported by grants from the Canadian Institute of Health Research to J.R.B.D. J.R.B.D. is an Alberta Heritage Foundation for Medical Research Scholar. J.N. is supported by doctoral studentships from the Mazankowski Alberta Heart Institute , Alberta Innovates Health Solutions (AiHS) , and the Canadian Diabetes Association (CDA) . P.C.K. is supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada , the CDA, and the AiHS. T.P. is supported by a postdoctoral fellowship from AiHS. D.F. is supported by a summer studentship from AiHS. The authors acknowledge the expert technical assistance of Amy Barr, Jamie Boisvenue, Donna Beker, Jody Levasseur, Grant Masson, Carrie-Lynn Soltys, and Ken Strynadka.

ASJC Scopus Subject Areas

Molecular Biology
Cardiology and Cardiovascular Medicine

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.yjmcc.2013.07.020

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title = "Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery",

abstract = "Although pre-clinical evidence has suggested that partial inhibition of myocardial fatty acid oxidation (FAO) and subsequent switch to greater glucose oxidation for ATP production can prevent ischemia/reperfusion injury, controversy about this approach persists. For example, mice with germline deletion of the FA transporter CD36, exhibited either impaired or unchanged post-ischemic functional recovery despite a 40-60% reduction in FAO rates. Because there are limitations to cardiac studies utilizing whole body CD36 knockout (total. CD36KO) mice, we have now generated an inducible and cardiomyocyte-specific CD36 KO (ic. CD36KO) mouse to better address the role of cardiomyocyte CD36 and its regulation of FAO and post-ischemic functional recovery. Four to six weeks following CD36 ablation, hearts from ic. CD36KO mice had significantly decreased FA uptake compared to controls, which was paralleled by significant reductions in intramyocardial triacylglycerol content. Analysis of cardiac energy metabolism using ex vivo working heart perfusions showed that reduced FAO rates were compensated by enhanced glucose oxidation in the hearts from ic. CD36KO mice. In contrast to the total. CD36KO mice, hearts from ic. CD36KO mice exhibited significantly improved functional recovery following ischemia/reperfusion (18. min of global no-flow ischemia followed by 40. min of aerobic reperfusion). This improved recovery was associated with lower calculated proton production prior to and following ischemia compared to controls. Moreover, the amount of ATP generated relative to cardiac work was significantly lower in the hearts from ic. CD36KO mice compared to controls, indicating significantly increased cardiac efficiency in the hearts from ic. CD36KO mice. These data provide genetic evidence that reduced FAO as a result of diminished CD36-mediated FA uptake improves post-ischemic cardiac efficiency and functional recovery. As such, targeting cardiomyocyte FA uptake and FAO via inhibition of CD36 in the adult myocardium may provide therapeutic benefit during ischemia-reperfusion.",

author = "Jeevan Nagendran and Thomas Pulinilkunnil and Kienesberger, {Petra C.} and Sung, {Miranda M.} and David Fung and Maria Febbraio and Dyck, {Jason R.B.}",

note = "Funding Information: This work was supported by grants from the Canadian Institute of Health Research to J.R.B.D. J.R.B.D. is an Alberta Heritage Foundation for Medical Research Scholar. J.N. is supported by doctoral studentships from the Mazankowski Alberta Heart Institute , Alberta Innovates Health Solutions (AiHS) , and the Canadian Diabetes Association (CDA) . P.C.K. is supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada , the CDA, and the AiHS. T.P. is supported by a postdoctoral fellowship from AiHS. D.F. is supported by a summer studentship from AiHS. The authors acknowledge the expert technical assistance of Amy Barr, Jamie Boisvenue, Donna Beker, Jody Levasseur, Grant Masson, Carrie-Lynn Soltys, and Ken Strynadka.",

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AU - Pulinilkunnil, Thomas

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AU - Sung, Miranda M.

AU - Fung, David

AU - Febbraio, Maria

AU - Dyck, Jason R.B.

N1 - Funding Information: This work was supported by grants from the Canadian Institute of Health Research to J.R.B.D. J.R.B.D. is an Alberta Heritage Foundation for Medical Research Scholar. J.N. is supported by doctoral studentships from the Mazankowski Alberta Heart Institute , Alberta Innovates Health Solutions (AiHS) , and the Canadian Diabetes Association (CDA) . P.C.K. is supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada , the CDA, and the AiHS. T.P. is supported by a postdoctoral fellowship from AiHS. D.F. is supported by a summer studentship from AiHS. The authors acknowledge the expert technical assistance of Amy Barr, Jamie Boisvenue, Donna Beker, Jody Levasseur, Grant Masson, Carrie-Lynn Soltys, and Ken Strynadka.

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N2 - Although pre-clinical evidence has suggested that partial inhibition of myocardial fatty acid oxidation (FAO) and subsequent switch to greater glucose oxidation for ATP production can prevent ischemia/reperfusion injury, controversy about this approach persists. For example, mice with germline deletion of the FA transporter CD36, exhibited either impaired or unchanged post-ischemic functional recovery despite a 40-60% reduction in FAO rates. Because there are limitations to cardiac studies utilizing whole body CD36 knockout (total. CD36KO) mice, we have now generated an inducible and cardiomyocyte-specific CD36 KO (ic. CD36KO) mouse to better address the role of cardiomyocyte CD36 and its regulation of FAO and post-ischemic functional recovery. Four to six weeks following CD36 ablation, hearts from ic. CD36KO mice had significantly decreased FA uptake compared to controls, which was paralleled by significant reductions in intramyocardial triacylglycerol content. Analysis of cardiac energy metabolism using ex vivo working heart perfusions showed that reduced FAO rates were compensated by enhanced glucose oxidation in the hearts from ic. CD36KO mice. In contrast to the total. CD36KO mice, hearts from ic. CD36KO mice exhibited significantly improved functional recovery following ischemia/reperfusion (18. min of global no-flow ischemia followed by 40. min of aerobic reperfusion). This improved recovery was associated with lower calculated proton production prior to and following ischemia compared to controls. Moreover, the amount of ATP generated relative to cardiac work was significantly lower in the hearts from ic. CD36KO mice compared to controls, indicating significantly increased cardiac efficiency in the hearts from ic. CD36KO mice. These data provide genetic evidence that reduced FAO as a result of diminished CD36-mediated FA uptake improves post-ischemic cardiac efficiency and functional recovery. As such, targeting cardiomyocyte FA uptake and FAO via inhibition of CD36 in the adult myocardium may provide therapeutic benefit during ischemia-reperfusion.

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Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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