Intracellular Na+ Concentration ([Na+]i) Is Elevated in Diabetic Hearts Due to Enhanced Na+-Glucose Cotransport.
Intracellular Na+ Concentration ([Na+]i) Is Elevated in Diabetic Hearts Due to Enhanced Na+-Glucose Cotransport.
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DOI：
10.1161/jaha.115.002183
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发表时间：
2015-08-27
影响因子：
5.4
通讯作者：
Despa S
中科院分区：
文献类型：
--
作者：
Lambert R;Srodulski S;Peng X;Margulies KB;Despa F;Despa S
细胞内Na+浓度（[Na +] i）调节心脏的Ca2+循环、收缩性、代谢和电稳定性。[Na+] i在心力衰竭中升高，导致心律失常和氧化应激。我们假设，2型糖尿病（T2D）中心肌细胞[Na +] i也增加，这是由于Na +-葡萄糖协同转运蛋白活性增强所致。为了验证这一假设，我们使用了来自患有T2D的人类和迟发性T2D的大鼠模型（HIP大鼠）的心肌组织。蛋白质印迹分析显示，与非糖尿病患者相比，T2D患者衰竭心脏中的Na +-葡萄糖协同转运蛋白表达增加（73 ± 13%），HIP大鼠心脏与野生型（WT）同窝仔相比（61 ± 8%）。[Na在静息（14.7 ± 0.9 vs 11.4 ± 0.7 mmol/L，WT）和电刺激期间（17.3 ± 0.8 vs 15.0 ± 0.7 mmol/L），HIP大鼠心肌细胞中的[Na +] i升高;然而，HIP和WT细胞中的Na +/K+泵功能相似，表明较高的[Na +] i是由于糖尿病心脏中Na+进入增强所致。事实上，与WT大鼠相比，HIP大鼠心肌细胞中的Na+内流显著更大（1.77 ± 0.11 mmol/L/min vs 1.29 ± 0.06 mmol/L/min）。用根皮苷或无葡萄糖溶液抑制Na +-葡萄糖协同转运蛋白可显著降低HIP心肌细胞的Na+内流（至1.20 ± 0.16 mmol/L/min），而对WT细胞无影响。根皮苷还显著降低了HIP心肌细胞的葡萄糖摄取（33 ± 9%），但在WT中没有，表明T2D心脏中葡萄糖摄取对Na +-葡萄糖协同转运蛋白的依赖性增加。2型糖尿病患者心肌细胞Na +-葡萄糖共转运增强，增加Na+内流，导致Na+超载。高[Na +] i可能有助于糖尿病心脏的血管生成和氧化应激。
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. 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. 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.