Lambert Rebekah, Srodulski Sarah, Peng Xiaoli, Margulies Kenneth B, Despa Florin, Despa Sanda
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (R.L., S.S., X.P., F.D., S.D.).
Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (K.B.M.).
J Am Heart Assoc. 2015 Aug 27;4(9):e002183. doi: 10.1161/JAHA.115.002183.
Intracellular Na(+) concentration ([Na(+)]i) regulates Ca(2+) 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.
细胞内钠离子浓度（[Na⁺]i）调节心脏的钙循环、收缩性、代谢及电稳定性。心力衰竭时[Na⁺]i升高，导致心律失常和氧化应激。我们推测2型糖尿病（T2D）时心肌细胞[Na⁺]i也会因钠-葡萄糖共转运体活性增强而升高。
为验证该假说，我们使用了T2D患者的心肌组织及晚发性T2D大鼠模型（HIP大鼠）。蛋白质印迹分析显示，与非糖尿病患者相比，T2D患者衰竭心脏中钠-葡萄糖共转运体表达增加（增加73±13%）；与野生型（WT）同窝仔鼠相比，HIP大鼠心脏中该转运体表达增加（增加61±8%）。HIP大鼠心肌细胞静息时[Na⁺]i升高（14.7±0.9 mmol/L，而WT为11.4±0.7 mmol/L），电刺激时也升高（17.3±0.8 mmol/L，而WT为15.0±0.7 mmol/L）；然而，HIP和WT细胞的钠钾泵功能相似，提示糖尿病心脏中较高的[Na⁺]i是由于钠内流增加所致。实际上，HIP大鼠心肌细胞的钠内流明显大于WT大鼠（每分钟1.77±0.11 mmol/L对1.29±0.06 mmol/L）。用根皮苷或无糖溶液抑制钠-葡萄糖共转运体可使HIP心肌细胞的钠内流大幅降低（至每分钟1.20±0.16 mmol/L），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（降低33±9%），但对WT细胞无影响，表明T2D心脏中葡萄糖摄取对钠-葡萄糖共转运体的依赖性增加。
T2D时心肌细胞钠-葡萄糖共转运增强，增加钠内流并导致钠超载。较高的[Na⁺]i可能促成糖尿病心脏的心律失常和氧化应激。
