Role of myocyte Na+ dysregulation in diabetic heart disease

摘要 2型糖尿病（T2 D）增加了心力衰竭、心律失常和心源性猝死的风险，即使在 无血管并发症。然而，对潜在的机制知之甚少。我们提出 糖尿病性心脏病的一个关键因素涉及肌细胞Na+失调。维护心脏 Na+稳态对维持心脏功能至关重要。肌细胞Na+浓度（[Na+]i）升高导致 氧化应激，并增加肌浆网（SR）Ca 2+泄漏，从而放大风险， 心律失常和促进心脏功能障碍。使用迟发型T2 D大鼠模型（HIP大鼠）， 心肌功能障碍和心律失常，我们最近发现，[Na+]i增加，在T2 D心脏。 出乎意料的是，较高的[Na+]i似乎是由Na+-葡萄糖协同转运蛋白的Na+进入增强引起的 同种型1（SGLT 1），以前被忽视的球员在细胞Na+稳态。此外，我们发现， T2 D患者心脏中SGLT 1表达与瘦型非糖尿病个体相比， 从糖尿病HIP大鼠与对照大鼠。心脏特异性SGLT 1过表达最近显示可导致 心肌肥厚和左心室功能障碍，而SGLT 1激活与心肌病有关。 由编码AMP活化蛋白激酶γ2亚基的基因突变引起。因此，证据 增强的SGLT 1活性损害心脏的说法越来越多，但对潜在的SGLT 1活性的影响知之甚少。 糖尿病性心肌病的发病机制及其作用。基于这些发现，我们假设SGLT 1 上调通过干扰T2 D患者的心脏重塑， 肌细胞Na+稳态失调。为了检验这一总体假设，我们将i）评估SGLT 1激活在 心肌细胞[Na+]i升高，随之产生氧化应激，更大的SR Ca 2+渗漏和自发性 T2 D中的后去极化，ii）测试SGLT 1上调是否是心肌对T2 D的适应不良， 胰岛素依赖性葡萄糖摄取受损，和iii）评估心脏中SGLT 1和[Na+]i是否升高 从患有T2 D的人身上。实验将结合联合收割机荧光成像，电生理学，生物化学，在 心脏功能的体内评估、药理学工具、T2 D和转基因动物模型以及人类 问题研究通过整合大鼠和人类心脏的生理学和药理学分析，该项目将 确定SGLT 1激活和Na+超负荷是否是糖尿病心脏病病理学中的关键事件 并将SGLT 1确定为T2 D患者心脏并发症的新治疗靶点。

ABSTRACT Type-2 diabetes (T2D) heightens the risk of heart failure, arrhythmias and sudden cardiac death, even in the absence of vascular complications. However, the underlying mechanisms are poorly understood. We propose that a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiac Na+ homeostasis is vital for preserving heart function. Elevated myocyte Na+ concentration ([Na+]i) causes oxidative stress and augments the sarcoplasmic reticulum (SR) Ca2+ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displays myocardial dysfunction and arrhythmias, we recently found that [Na+]i is increased in T2D hearts. Unexpectedly, higher [Na+]i seems to be caused by enhanced Na+ entry through the Na+-glucose cotransporter isoform 1 (SGLT1), a previously ignored player in cellular Na+ homeostasis. Furthermore, we found higher SGLT1 expression in hearts from patients with T2D compared to lean, non-diabetic individuals and in hearts from diabetic HIP rats vs. control rats. Cardiac-specific SGLT1 overexpression was recently shown to cause hypertrophy and left-ventricular dysfunction, while SGLT1 activation has been linked to the cardiomyopathy caused by mutations in the gene encoding the γ2 subunit of AMP-activated protein kinase. Thus, the evidence that enhanced SGLT1 activity damages the heart is mounting, but little is known about the underlying mechanisms and its role in diabetic cardiomyopathy. Based on these findings, we hypothesize that SGLT1 upregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D by perturbing myocyte Na+ dyshomeostasis. To test this overall hypothesis, we will i) assess the role of SGLT1 activation in the myocyte [Na+]i rise and consequent oxidative stress, larger SR Ca2+ leak and spontaneous afterdepolarizations in T2D, ii) test whether SGLT1 upregulation is a maladaptation of the myocardium to impaired insulin-dependent glucose uptake, and iii) assess whether SGLT1 and [Na+]i are elevated in hearts from humans with T2D. Experiments will combine fluorescence imaging, electrophysiology, biochemistry, in vivo assessment of heart function, pharmacological tools, T2D and transgenic animal models and human studies. By integrating physiological and pharmacological analyses in rat and human hearts, this project will establish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart disease and will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.