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Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats

BACKGROUND: Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) modulates the oxidative state and cytosolic Ca(2+) regulation. Thus, we investigated how T2D affects mitochondrial Ca(2+) fluxes, the downs...

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Autores principales: Velmurugan, Sathya, Liu, Ting, Chen, Kuey C., Despa, Florin, O'Rourke, Brian, Despa, Sanda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382117/
https://www.ncbi.nlm.nih.gov/pubmed/37421267
http://dx.doi.org/10.1161/JAHA.123.029997
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author Velmurugan, Sathya
Liu, Ting
Chen, Kuey C.
Despa, Florin
O'Rourke, Brian
Despa, Sanda
author_facet Velmurugan, Sathya
Liu, Ting
Chen, Kuey C.
Despa, Florin
O'Rourke, Brian
Despa, Sanda
author_sort Velmurugan, Sathya
collection PubMed
description BACKGROUND: Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) modulates the oxidative state and cytosolic Ca(2+) regulation. Thus, we investigated how T2D affects mitochondrial Ca(2+) fluxes, the downstream consequences on myocyte function, and the effects of normalizing mitochondrial Ca(2+) transport. METHODS AND RESULTS: We compared myocytes/hearts from transgenic rats with late‐onset T2D (rats that develop late‐onset T2D due to heterozygous expression of human amylin in the pancreatic β‐cells [HIP] model) and their nondiabetic wild‐type (WT) littermates. [Ca(2+)](m) was significantly lower in myocytes from diabetic HIP rats compared with WT cells. Ca(2+) extrusion through the mitochondrial Na(+)/Ca(2+) exchanger (mitoNCX) was elevated in HIP versus WT myocytes, particularly at moderate and high [Ca(2+)](m), while mitochondrial Ca(2+) uptake was diminished. Mitochondrial Na(+) concentration was comparable in WT and HIP rat myocytes and remained remarkably stable while manipulating mitoNCX activity. Lower [Ca(2+)](m) was associated with oxidative stress, increased sarcoplasmic reticulum Ca(2+) leak in the form of Ca(2+) sparks, and mitochondrial dysfunction in T2D hearts. MitoNCX inhibition with CGP‐37157 reduced oxidative stress, Ca(2+) spark frequency, and stress‐induced arrhythmias in HIP rat hearts while having no significant effect in WT rats. In contrast, activation of the mitochondrial Ca(2+) uniporter with SB‐202190 enhanced spontaneous sarcoplasmic reticulum Ca(2+) release and had no significant effect on arrhythmias in both WT and HIP rat hearts. CONCLUSIONS: [Ca(2+)](m) is reduced in myocytes from rats with T2D due to a combination of exacerbated mitochondrial Ca(2+) extrusion through mitoNCX and impaired mitochondrial Ca(2+) uptake. Partial mitoNCX inhibition limits sarcoplasmic reticulum Ca(2+) leak and arrhythmias in T2D hearts, whereas mitochondrial Ca(2+) uniporter activation does not.
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spelling pubmed-103821172023-07-29 Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats Velmurugan, Sathya Liu, Ting Chen, Kuey C. Despa, Florin O'Rourke, Brian Despa, Sanda J Am Heart Assoc Original Research BACKGROUND: Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) modulates the oxidative state and cytosolic Ca(2+) regulation. Thus, we investigated how T2D affects mitochondrial Ca(2+) fluxes, the downstream consequences on myocyte function, and the effects of normalizing mitochondrial Ca(2+) transport. METHODS AND RESULTS: We compared myocytes/hearts from transgenic rats with late‐onset T2D (rats that develop late‐onset T2D due to heterozygous expression of human amylin in the pancreatic β‐cells [HIP] model) and their nondiabetic wild‐type (WT) littermates. [Ca(2+)](m) was significantly lower in myocytes from diabetic HIP rats compared with WT cells. Ca(2+) extrusion through the mitochondrial Na(+)/Ca(2+) exchanger (mitoNCX) was elevated in HIP versus WT myocytes, particularly at moderate and high [Ca(2+)](m), while mitochondrial Ca(2+) uptake was diminished. Mitochondrial Na(+) concentration was comparable in WT and HIP rat myocytes and remained remarkably stable while manipulating mitoNCX activity. Lower [Ca(2+)](m) was associated with oxidative stress, increased sarcoplasmic reticulum Ca(2+) leak in the form of Ca(2+) sparks, and mitochondrial dysfunction in T2D hearts. MitoNCX inhibition with CGP‐37157 reduced oxidative stress, Ca(2+) spark frequency, and stress‐induced arrhythmias in HIP rat hearts while having no significant effect in WT rats. In contrast, activation of the mitochondrial Ca(2+) uniporter with SB‐202190 enhanced spontaneous sarcoplasmic reticulum Ca(2+) release and had no significant effect on arrhythmias in both WT and HIP rat hearts. CONCLUSIONS: [Ca(2+)](m) is reduced in myocytes from rats with T2D due to a combination of exacerbated mitochondrial Ca(2+) extrusion through mitoNCX and impaired mitochondrial Ca(2+) uptake. Partial mitoNCX inhibition limits sarcoplasmic reticulum Ca(2+) leak and arrhythmias in T2D hearts, whereas mitochondrial Ca(2+) uniporter activation does not. John Wiley and Sons Inc. 2023-07-08 /pmc/articles/PMC10382117/ /pubmed/37421267 http://dx.doi.org/10.1161/JAHA.123.029997 Text en © 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Velmurugan, Sathya
Liu, Ting
Chen, Kuey C.
Despa, Florin
O'Rourke, Brian
Despa, Sanda
Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats
title Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats
title_full Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats
title_fullStr Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats
title_full_unstemmed Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats
title_short Distinct Effects of Mitochondrial Na(+)/Ca(2+) Exchanger Inhibition and Ca(2+) Uniporter Activation on Ca(2+) Sparks and Arrhythmogenesis in Diabetic Rats
title_sort distinct effects of mitochondrial na(+)/ca(2+) exchanger inhibition and ca(2+) uniporter activation on ca(2+) sparks and arrhythmogenesis in diabetic rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382117/
https://www.ncbi.nlm.nih.gov/pubmed/37421267
http://dx.doi.org/10.1161/JAHA.123.029997
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