Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes

Abstract Empagliflozin, a sodium-glucose co-transporter (SGLT) inhibitor, reduces heart failure and sudden cardiac death but the underlying mechanisms remain elusive. In cardiomyocytes, SGLT1 and SGLT2 expression is upregulated in diabetes mellitus, heart failure, and myocardial infarction. We hypot...

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Autores principales:	Kwong-Man Ng, Yee-Man Lau, Vidhu Dhandhania, Zhu-Jun Cai, Yee-Ki Lee, Wing-Hon Lai, Hung-Fat Tse, Chung-Wah Siu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	hiPSC-derived Cardiomyocytes Sodium Glucose Co-transporter (SGLT) HG Treatment SGLT1 Expression Diabetic Cardiomyopathy Medicine R Science Q
Acceso en línea:	https://doaj.org/article/645fea2d98e649728a8b8a8d073e5a30
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spelling	oai:doaj.org-article:645fea2d98e649728a8b8a8d073e5a302021-12-02T15:07:57ZEmpagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes10.1038/s41598-018-33293-22045-2322https://doaj.org/article/645fea2d98e649728a8b8a8d073e5a302018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33293-2https://doaj.org/toc/2045-2322Abstract Empagliflozin, a sodium-glucose co-transporter (SGLT) inhibitor, reduces heart failure and sudden cardiac death but the underlying mechanisms remain elusive. In cardiomyocytes, SGLT1 and SGLT2 expression is upregulated in diabetes mellitus, heart failure, and myocardial infarction. We hypothesise that empagliflozin exerts direct effects on cardiomyocytes that attenuate diabetic cardiomyopathy. To test this hypothesis, cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were used to test the potential effects of empagliflozin on neutralization of cardiac dysfunction induced by diabetic-like cultures. Our results indicated that insulin-free high glucose culture significantly increased the size of and NPPB, SGLT1 and SGLT2 expression of hiPSC-derived cardiomyocytes. In addition, high glucose-treated hiPSC-derived cardiomyocytes exhibited reduced contractility regardless of the increased calcium transient capacity. Interestingly, application of empagliflozin before or after high glucose treatment effectively reduced the high glucose-induced cardiac abnormalities. Since application of empagliflozin did not significantly alter viability or glycolytic capacity of the hiPSC-derived cardiomyocytes, it is plausible that empagliflozin exerts its effects via the down-regulation of SGLT1, SGLT2 and GLUT1 expression. These observations provide supportive evidence that may help explain its unexpected benefit observed in the EMPA-REG trial.Kwong-Man NgYee-Man LauVidhu DhandhaniaZhu-Jun CaiYee-Ki LeeWing-Hon LaiHung-Fat TseChung-Wah SiuNature PortfolioarticlehiPSC-derived CardiomyocytesSodium Glucose Co-transporter (SGLT)HG TreatmentSGLT1 ExpressionDiabetic CardiomyopathyMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	hiPSC-derived Cardiomyocytes Sodium Glucose Co-transporter (SGLT) HG Treatment SGLT1 Expression Diabetic Cardiomyopathy Medicine R Science Q
spellingShingle	hiPSC-derived Cardiomyocytes Sodium Glucose Co-transporter (SGLT) HG Treatment SGLT1 Expression Diabetic Cardiomyopathy Medicine R Science Q Kwong-Man Ng Yee-Man Lau Vidhu Dhandhania Zhu-Jun Cai Yee-Ki Lee Wing-Hon Lai Hung-Fat Tse Chung-Wah Siu Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes
description	Abstract Empagliflozin, a sodium-glucose co-transporter (SGLT) inhibitor, reduces heart failure and sudden cardiac death but the underlying mechanisms remain elusive. In cardiomyocytes, SGLT1 and SGLT2 expression is upregulated in diabetes mellitus, heart failure, and myocardial infarction. We hypothesise that empagliflozin exerts direct effects on cardiomyocytes that attenuate diabetic cardiomyopathy. To test this hypothesis, cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were used to test the potential effects of empagliflozin on neutralization of cardiac dysfunction induced by diabetic-like cultures. Our results indicated that insulin-free high glucose culture significantly increased the size of and NPPB, SGLT1 and SGLT2 expression of hiPSC-derived cardiomyocytes. In addition, high glucose-treated hiPSC-derived cardiomyocytes exhibited reduced contractility regardless of the increased calcium transient capacity. Interestingly, application of empagliflozin before or after high glucose treatment effectively reduced the high glucose-induced cardiac abnormalities. Since application of empagliflozin did not significantly alter viability or glycolytic capacity of the hiPSC-derived cardiomyocytes, it is plausible that empagliflozin exerts its effects via the down-regulation of SGLT1, SGLT2 and GLUT1 expression. These observations provide supportive evidence that may help explain its unexpected benefit observed in the EMPA-REG trial.
format	article
author	Kwong-Man Ng Yee-Man Lau Vidhu Dhandhania Zhu-Jun Cai Yee-Ki Lee Wing-Hon Lai Hung-Fat Tse Chung-Wah Siu
author_facet	Kwong-Man Ng Yee-Man Lau Vidhu Dhandhania Zhu-Jun Cai Yee-Ki Lee Wing-Hon Lai Hung-Fat Tse Chung-Wah Siu
author_sort	Kwong-Man Ng
title	Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes
title_short	Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes
title_full	Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes
title_fullStr	Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes
title_full_unstemmed	Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes
title_sort	empagliflozin ammeliorates high glucose induced-cardiac dysfuntion in human ipsc-derived cardiomyocytes
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/645fea2d98e649728a8b8a8d073e5a30
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Empagliflozin Ammeliorates High Glucose Induced-Cardiac Dysfuntion in Human iPSC-Derived Cardiomyocytes

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