Role of myocyte Na+ dysregulation in diabetic heart disease

肌细胞钠离子失调在糖尿病心脏病中的作用

• 批准号: 9983150
• 负责人: Sanda Despa
• 金额: $ 41.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983150
• 关键词: 5' -AMP-activated protein kinase; Animal Model; Animals; Arrhythmia; Automobile Driving; Biochemistry; Blood Vessels; Cardiac; Cardiomyopathies; Diabetes Mellitus; Electric Stimulation; Electrophysiology (science); Event; Genes; Glucose; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Hyperglycemia; Hypertrophy; Impairment; Individual; Insulin; Insulin Resistance; Kidney; Left Ventricular Dysfunction; Link; Maintenance; Mediating; Messenger RNA; Mitochondria; Modeling; Mus; Muscle Cells; Mutation; Myocardial; Myocardial dysfunction; Myocardium; Na(+)-K(+)-Exchanging ATPase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathology; Patients; Pharmacology; Phase; Physiological; Prediabetes syndrome; Protein Isoforms; Proteins; Rattus; Regulation; Rest; Risk; Role; Sarcoplasmic Reticulum; Structure; Testing; Thinness; Tissues; Transgenic Animals; Transgenic Mice; Translating; Up-Regulation; Work; base; cardioprotection; db/db mouse; diabetic; diabetic cardiomyopathy; experimental study; fluorescence imaging; glucose uptake; heart damage; heart function; heart preservation; improved; in vivo; insulin sensitizing drugs; insulin signaling; new therapeutic target; non-diabetic; overexpression; prevent; sudden cardiac death; tool

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.

抽象的 2型糖尿病（T2D）甚至在 但是，缺乏血管汇编 导致糖尿病心脏病的这种贡献涉及心肌细胞NA+失调。 NA+稳态对于保留心脏功能至关重要。 氧化应激并增加肌质网（SR）CA2+泄漏，从而扩大了风险 心律不齐和心脏功能障碍。 心肌功能障碍和心律不齐，我们最近发现[Na+] I在T2D心脏中增加。 出乎意料的是，较高的[na+]似乎是由进入Na+ - 葡萄糖共转运蛋白所引起的 同工型1（SGLT1），以前是细胞Na+体内稳态中的忽略玩家。 与精益，非糖尿病个体和心脏相比，T2D患者心脏中的SGLT1表达 从糖尿病的髋关节大鼠与对照大鼠。 肥大和左心室功能障碍，而SGLT1激活已成为心肌病 由AMP激活蛋白激酶的γ2亚基的基因中的突变引起 增强的SGLT1活动会损害心脏的安装，但对基础知之甚少 根据发现的机制和糖尿病心肌病的作用。 上调有助于通过与T2D进行心脏重塑的多因素机制 肌细胞Na+ Dyshomeostasis。 心肌[na+]我上升和解决氧化应激，较大的SR Ca2+泄漏和自发性 t2d中的脱离后，ii）测试sglt1上调是否是心肌疾病的疾病 胰岛素依赖性葡萄糖的摄取受损，iii）评估SGLT1和[Na+] I是否在心脏中升高 来自T2D的人类将结合荧光成像，电生理学，生物化学 心脏功能，药理学工具，T2D和转基因动物模型以及人类的体内评估 通过整合大鼠和人心的物理学和药物分析的研究，该项目将 确定SGLT1激活和NA+超负荷是否是糖尿病心脏病病理学的关键事件 并将识别SGLT1是T2D特定性CADCIACC并发症的新治疗靶点。