Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport

Rebekah Lambert, Sarah Srodulskic, Xiaoli Peng, Kenneth B. Margulies, Florin Despa, Sanda Despa

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background-Intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, contractility, metabolism, and electrical stability of the heart. [Na+]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na+]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na+-glucose cotransporter. Methods and Results-To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na+-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13%) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8%). [Na+]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na+/K+-pump function was similar in HIP and WT cells, suggesting that higher [Na+]i is due to enhanced Na+ entry in diabetic hearts. Indeed, Na+ influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na+-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na+ influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9%) but not in WT, indicating an increased reliance on the Na+- glucose cotransporter for glucose uptake in T2D hearts. Conclusions-Myocyte Na+-glucose cotransport is enhanced in T2D, which increases Na+ influx and causes Na+ overload. Higher [Na+]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.

Original languageEnglish (US)
Article numbere002183
JournalJournal of the American Heart Association
Volume4
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

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Muscle Cells
Type 2 Diabetes Mellitus
Glucose
Phlorhizin
Oxidative Stress
Electric Stimulation
Cardiac Arrhythmias
Heart Failure
Western Blotting

Keywords

  • Heart
  • Intracellular Na concentration
  • Na-glucose cotransporter
  • Type 2 diabetes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport. / Lambert, Rebekah; Srodulskic, Sarah; Peng, Xiaoli; Margulies, Kenneth B.; Despa, Florin; Despa, Sanda.

In: Journal of the American Heart Association, Vol. 4, No. 9, e002183, 01.09.2015.

Research output: Contribution to journalArticle

Lambert, Rebekah ; Srodulskic, Sarah ; Peng, Xiaoli ; Margulies, Kenneth B. ; Despa, Florin ; Despa, Sanda. / Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport. In: Journal of the American Heart Association. 2015 ; Vol. 4, No. 9.
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abstract = "Background-Intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, contractility, metabolism, and electrical stability of the heart. [Na+]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na+]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na+-glucose cotransporter. Methods and Results-To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na+-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13{\%}) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8{\%}). [Na+]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na+/K+-pump function was similar in HIP and WT cells, suggesting that higher [Na+]i is due to enhanced Na+ entry in diabetic hearts. Indeed, Na+ influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na+-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na+ influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9{\%}) but not in WT, indicating an increased reliance on the Na+- glucose cotransporter for glucose uptake in T2D hearts. Conclusions-Myocyte Na+-glucose cotransport is enhanced in T2D, which increases Na+ influx and causes Na+ overload. Higher [Na+]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.",
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T1 - Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport

AU - Lambert, Rebekah

AU - Srodulskic, Sarah

AU - Peng, Xiaoli

AU - Margulies, Kenneth B.

AU - Despa, Florin

AU - Despa, Sanda

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background-Intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, contractility, metabolism, and electrical stability of the heart. [Na+]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na+]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na+-glucose cotransporter. Methods and Results-To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na+-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13%) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8%). [Na+]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na+/K+-pump function was similar in HIP and WT cells, suggesting that higher [Na+]i is due to enhanced Na+ entry in diabetic hearts. Indeed, Na+ influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na+-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na+ influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9%) but not in WT, indicating an increased reliance on the Na+- glucose cotransporter for glucose uptake in T2D hearts. Conclusions-Myocyte Na+-glucose cotransport is enhanced in T2D, which increases Na+ influx and causes Na+ overload. Higher [Na+]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.

AB - Background-Intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, contractility, metabolism, and electrical stability of the heart. [Na+]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na+]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na+-glucose cotransporter. Methods and Results-To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na+-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13%) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8%). [Na+]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na+/K+-pump function was similar in HIP and WT cells, suggesting that higher [Na+]i is due to enhanced Na+ entry in diabetic hearts. Indeed, Na+ influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na+-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na+ influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9%) but not in WT, indicating an increased reliance on the Na+- glucose cotransporter for glucose uptake in T2D hearts. Conclusions-Myocyte Na+-glucose cotransport is enhanced in T2D, which increases Na+ influx and causes Na+ overload. Higher [Na+]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts.

KW - Heart

KW - Intracellular Na concentration

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KW - Type 2 diabetes

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