Role of myocyte Na+ dysregulation in diabetic heart disease
Role of myocyte Na+ dysregulation in diabetic heart disease
批准号:
9383524
负责人:
Sanda Despa
金额:
$45.04万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-01 至 2021-07-31
关键词:
5&apos-AMP-activated protein kinaseAnimal ModelAnimalsArrhythmiaAutomobile DrivingBiochemistryBlood VesselsCardiacCardiomyopathiesDiabetes MellitusElectric StimulationElectrophysiology (science)EventGenesGlucoseHeartHeart DiseasesHeart failureHomeostasisHumanHyperglycemiaHypertrophyImpairmentIndividualInsulinInsulin ResistanceKidneyLeft Ventricular DysfunctionLinkMaintenanceMediatingMessenger RNAMitochondriaModelingMusMuscle CellsMutationMyocardialMyocardial dysfunctionMyocardiumNa(+)-K(+)-Exchanging ATPaseNon-Insulin-Dependent Diabetes MellitusObesityOxidative StressPathologyPatientsPharmacologyPhasePhysiologicalPrediabetes syndromeProtein IsoformsProteinsRattusRegulationRestRiskRoleSarcoplasmic ReticulumStructureTestingThinnessTissuesTransgenic AnimalsTransgenic MiceTranslatingUp-RegulationWorkbasedb/db mousediabeticdiabetic cardiomyopathyexperimental studyfluorescence imagingglucose uptakeheart functionimprovedin vivoinjuredinsulin sensitizing drugsinsulin signalingnew therapeutic targetnon-diabeticoverexpressionpreventsudden cardiac deathtool
中文摘要
摘要
2型糖尿病(T2D)会增加心力衰竭、心律失常和心脏性猝死的风险,即使在
无血管并发症。然而,人们对其潜在的机制知之甚少。我们建议
糖尿病心脏病的一个关键因素与心肌细胞钠调节失调有关。心脏维持术
钠稳态对于保护心脏功能是至关重要的。心肌细胞钠浓度([Na]i)升高导致
氧化应激并增加肌浆网(SR)钙泄漏,从而放大
心律失常和促进心脏功能障碍。使用迟发性T2D的大鼠模型(髋部大鼠)
心肌功能障碍和心律失常,我们最近发现在T2D心脏中[Na]i升高。
出乎意料的是,较高的[Na]i似乎是由钠-葡萄糖共转运体增强的钠进入引起的
异构体1(SGLT1),一个以前被忽视的细胞钠稳态的参与者。此外,我们发现更高的
T2D患者心脏中SGLT1的表达与消瘦的非糖尿病患者和心脏的比较
来自糖尿病髋部大鼠和对照组大鼠。心脏特异性SGLT1的过度表达最近被证明是导致
肥厚和左心功能不全,而SGLT1激活与心肌病有关
由编码AMP激活的蛋白激酶γ2亚单位的基因突变引起。因此,有证据表明
这种增强的SGLT1活性对心脏的损害正在加剧,但对其潜在的影响知之甚少
糖尿病心肌病的发病机制及其作用。基于这些发现,我们假设SGLT1
上调参与T2D心脏重构的多因素机制
心肌细胞钠代谢紊乱。为了检验这一总体假设,我们将i)评估SGLT1激活在
心肌细胞[Na]i升高,导致氧化应激,肌浆网钙离子漏出增多,自发性
T2D的后除极,II)测试SGLT1上调是否是心肌对
受损的胰岛素依赖的葡萄糖摄取,以及iii)评估SGLT1和[Na]i是否在心脏中升高
来自患有T2D的人类。实验将结合荧光成像、电生理学、生物化学、
心功能的活体评估、药理工具、T2D和转基因动物模型以及人类
学习。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SGLT1激活和钠超载是否是糖尿病心脏病病理中的关键事件
并将SGLT1确定为T2D患者心脏并发症的新治疗靶点。
英文摘要
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.
期刊论文(0)
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会议论文
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依托单位:
海外基金